rs4253047

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000124.4(ERCC6):c.1337G>A(p.Gly446Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,612,966 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0098 ( 9 hom., cov: 32)

Exomes 𝑓: 0.014 ( 154 hom. )

Consequence

ERCC6
NM_000124.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.40

Publications

18 publications found

Variant links:

Genes affected

ERCC6 (HGNC:3438): (ERCC excision repair 6, chromatin remodeling factor) This gene encodes a DNA-binding protein that is important in transcription-coupled excision repair. The encoded protein has ATP-stimulated ATPase activity, interacts with several transcription and excision repair proteins, and may promote complex formation at DNA repair sites. Mutations in this gene are associated with Cockayne syndrome type B and cerebrooculofacioskeletal syndrome 1. Alternative splicing occurs between a splice site from exon 5 of this gene to the 3' splice site upstream of the open reading frame (ORF) of the adjacent gene, piggyback-derived-3 (GeneID:267004), which activates the alternative polyadenylation site downstream of the piggyback-derived-3 ORF. The resulting transcripts encode a fusion protein that shares sequence with the product of each individual gene. [provided by RefSeq, Mar 2016]

ERCC6 links:

PGBD3 (HGNC:19400): (piggyBac transposable element derived 3) This gene is a member of a small family of genes derived from piggyBac transposable elements. The encoded protein contains a zinc-ribbon domain characteristic of transposon-derived proteins and may function as a regulator of transcription. Alternative splicing occurs between a splice site from exon 5 of the adjacent upstream gene 'excision repair cross-complementation group 6' (ERCC6, GeneID: 2074) and the 3' splice site upstream of the open reading frame (ORF) of this gene, which activates the alternative polyadenylation site downstream of the piggyback-derived-3 ORF. The resulting transcripts encode a fusion protein that shares sequence with the product of each individual gene. Pseudogenes for this gene are defined on chromosomes 4, 5 and 12. [provided by RefSeq, Mar 2016]

PGBD3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0059863925).

BP6

Variant 10-49524093-C-T is Benign according to our data. Variant chr10-49524093-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00982 (1494/152068) while in subpopulation NFE AF = 0.0151 (1027/67970). AF 95% confidence interval is 0.0143. There are 9 homozygotes in GnomAd4. There are 728 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC6	NM_000124.4 link	c.1337G>A	p.Gly446Asp	missense_variant	Exon 5 of 21	ENST00000355832.10	NP_000115.1	Q03468-1Q59FF6
ERCC6	NM_001277058.2 link	c.1337G>A	p.Gly446Asp	missense_variant	Exon 5 of 6	ENST00000447839.7	NP_001263987.1	P0DP91-1A8K4Q3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC6	ENST00000355832.10 link	c.1337G>A	p.Gly446Asp	missense_variant	Exon 5 of 21	1	NM_000124.4	ENSP00000348089.5		Q03468-1
ERCC6	ENST00000447839.7 link	c.1337G>A	p.Gly446Asp	missense_variant	Exon 5 of 6	2	NM_001277058.2	ENSP00000387966.2		P0DP91-1

Frequencies

GnomAD3 genomes

AF:

0.00984

AC:

1495

AN:

151950

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00254

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00905

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0172

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0151

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00953

AC:

2367

AN:

248338

AF XY:

0.00962

show subpopulations

Gnomad AFR exome

AF:

0.00283

Gnomad AMR exome

AF:

0.00662

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0184

Gnomad NFE exome

AF:

0.0140

Gnomad OTH exome

AF:

0.00899

GnomAD4 exome

AF:

0.0140

AC:

20401

AN:

1460898

Hom.:

154

Cov.:

AF XY:

0.0135

AC XY:

9806

AN XY:

726804

show subpopulations

African (AFR)

AF:

0.00242

AC:

AN:

33474

American (AMR)

AF:

0.00675

AC:

302

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39696

South Asian (SAS)

AF:

0.00281

AC:

242

AN:

86252

European-Finnish (FIN)

AF:

0.0178

AC:

934

AN:

52546

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0163

AC:

18176

AN:

1111926

Other (OTH)

AF:

0.0108

AC:

655

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

1335

2670

4004

5339

6674

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

706

1412

2118

2824

3530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00982

AC:

1494

AN:

152068

Hom.:

Cov.:

AF XY:

0.00979

AC XY:

728

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00253

AC:

105

AN:

41472

American (AMR)

AF:

0.00903

AC:

138

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00166

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0172

AC:

182

AN:

10566

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0151

AC:

1027

AN:

67970

Other (OTH)

AF:

0.0114

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

155

232

310

387

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0120

Hom.:

Bravo

AF:

0.00870

TwinsUK

AF:

0.0159

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0141

AC:

121

ExAC

AF:

0.00946

AC:

1148

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0133

EpiControl

AF:

0.0143

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 19, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 25, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ERCC6: BP4, BS1, BS2; PGBD3: BS1, BS2 -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

COFS syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cockayne syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Macular degeneration

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.059

T;.;.

Eigen

Benign

-0.053

Eigen_PC

Benign

-0.052

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.71

T;.;T

MetaRNN

Benign

0.0060

T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.6

M;.;.

PhyloP100

2.4

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.53

N;N;N

REVEL

Benign

0.058

Sift

Benign

0.61

T;D;D

Sift4G

Benign

0.54

T;T;T

Polyphen

0.48

P;.;.

Vest4

0.33

MVP

0.75

MPC

0.17

ClinPred

0.032

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.035

gMVP

0.16

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over