Table 1 Non-coding candidate variants and putative target genes

From: A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders

Pedigree

CCDD

Sporadic vs familial

Isolated vs syndromic

Monoallelic vs biallelic variant(s)

Non-coding variant (hg38)

Peak Type

Nearest gene

Target gene

Distance to target (kb)

Reporter ID

Peak to gene r

Peak to gene FDR

gnomAD allele frequency

Predicted mechanism

SAD Z-score

Target gene loeufa

Target gene pHaplob

Target gene pTriploc

Non-coding Z-scored

S25

CFEOM

S

I

M

chr10:129794079 TTGAG > T

D

EBF3

EBF3†

(±DRS)

170

hs2776

0.24

2.90E-07

8.37E-05

LoF

−11.77

0.15

1.00

1.00

3.10

S176

MGJW

F, AD

I

M

chr10:129884231 C > A

I

EBF3

EBF3† (±DRS)

-

hs2775

0.29

3.89E-10

4.88E-05

GoF

0.11

0.15

1.00

1.00

3.74

S95

Ptosis

F, AD

Cr

M

chr10:129944464 G > C

I

EBF3

EBF3† (±DRS)

-

hs2774

0.21

7.76E-06

-

GoF

0.98

0.15

1.00

1.00

5.14

S12

DRS

S

Ca

B(h)

chr11:72394626 C > G

I

CLPB

PHOX2A (+CFEOM)

156

-

0.26

1.09E-08

1.41E-03

GoF

0.18

0.80

0.76

0.98

2.32

S32

Ptosis

F, AD

I

M

chr2:175005662 C > T††

P

CHN1

CHN1 (+DRS)

-

-

0.48

1.31E-28

1.39E-04

LoF

−0.38

0.57

0.41

0.72

2.59

S251

CFEOM/DRS

F, AD

I

M

chr2:175006051 GCTT > G††

P

CHN1

CHN1 (+DRS)

-

-

0.48

1.31E-28

-

GoF

2.29

0.57

0.41

0.72

2.08

S230

DRS

S

I

M

chr20:40866929-40945626†††

D

TOP1

MAFB (+DRS)

256

hs2769

hs2770

0.23*

1.19E-05*

-

-

-

0.40

0.94

1.00

2.19*

S205

CFP

S

I

B(ch)

chr5:51172762 T > A

D

ISL1

ISL1

221

hs1321

0.74

1.36E-86

2.26E-03

LoF

−0.41

0.23

0.95

0.85

−2.28

S205

CFP

S

I

B(ch)

chr5:51172961 T > G

D

ISL1

ISL1

221

hs1321

0.74

1.36E-86

2.33E-03

LoF

−0.12

0.23

0.95

0.85

−2.28

S190

DRS

S

I

B(ch)

chr22:27493955-27497536††,†††

D

MN1

MN1

307

hs2757

-

-

1.38E-04

-

-

0.48

0.99

0.92

0.29*

S238

DRS

S DRS, F, AD SNHL

SNHL

B(ch)

chr22:27493955-27497536††,†††

D

MN1

MN1

307

hs2757

-

-

1.38E-04

-

-

0.48

0.99

0.92

0.29*

S191

DRS

S

I

B(ch)

chr17:1455690 G > A††

I

CRK

CRK

-

-

-

-

-

GoF

0.44

0.34

0.97

1.00

0.30

S191

DRS

S

I

B(ch)

chr17:1456361 G > A††

P

CRK

CRK

-

-

-

-

1.51E-03

LoF

−1.24

0.34

0.97

1.00

-

S211

DRS

S

I

B(ch)

chr17:1455565 C > T††

I

CRK

CRK

-

-

-

-

1.19E-04

GoF

0.49

0.34

0.97

1.00

0.30

S211

DRS

S

I

B(ch)

chr17:1456436 G C > G††

P

CRK

CRK

-

-

-

-

3.77E-04

LoF

−12.28

0.34

0.97

1.00

-

S211

DRS

S

I

B(ch)

chr17:1456438 G > A††

P

CRK

CRK

-

-

-

-

3.77E-04

LoF

−2.06

0.34

0.97

1.00

-

WL

DRS

F, 2 sibs

I

M

chr17:48003752 A > C††

D

CDK5RAP3

CDK5RAP3

22

hs2777

0.57

8.04E-43

-

GoF

4.31

0.97

0.24

0.54

1.94

S174

MBS

S

I

B(ch)

chr17:48003557 C > G††

D

CDK5RAP3

CDK5RAP3

22

hs2777

0.57

8.04E-43

4.04E-03

LoF

−0.15

0.97

0.24

0.54

1.94

S174

MBS

S

I

B(ch)

chr17:48003826 C > T††

D

CDK5RAP3

CDK5RAP3

22

hs2777

0.57

8.04E-43

9.42E-04

GoF

1.69

0.97

0.24

0.54

1.94

S156

CFP

F, AD

I

M

chr3:128459417 G > C††

D

DNAJB8

GATA2

7

-

0.28

6.08E-10

-

LoF

−4.88

0.34

0.98

0.87

-

S180

CFP

F, AD

I

M

chr3:128459454 A > G††

D

DNAJB8

GATA2

7

-

0.28

6.08E-10

3.95E-05

GoF

2.88

0.34

0.98

0.87

-

S194

CFP

F, AD

I

M

chr3:128459455 G > A††

D

DNAJB8

GATA2

7

-

0.28

6.08E-10

-

GoF

11.40

0.34

0.98

0.87

-

  1. S sporadic, F familial, AD autosomal dominant inheritance pattern, SNHL sensorineural hearing loss, M monoallelic, B biallelic, h homozygous, ch compound het, ± denotes that reported individuals with variants in the gene have a syndromic phenotype and a subset also have the stated CCDD phenotype, + denotes an established CCDD gene for stated phenotype, I intronic, P promoter, D distal, LoF loss-of-function, GoF gain-of-function, I isolated, Cr craniofacial, Ca cardiac
  2. aCoding loss-of-function intolerance—https://doi.org/10.1038/s41586-020-2308-7
  3. bCoding dosage sensitivity—https://doi.org/10.1016/j.cell.2022.06.036
  4. cNon-coding mutational constraint (1 kb windows)—https://doi.org/10.1101/2022.03.20.485034
  5. *mean value across deleted interval
  6. †Multi-hit gene; ††Multi-hit peak; †††non-coding deletion
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