2-127259402-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000122.2(ERCC3):c.2111C>T(p.Ser704Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00249 in 1,614,128 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S704S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 9 hom. )

Consequence

ERCC3
NM_000122.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2B:8O:1

Conservation

PhyloP100: 5.32

Publications

21 publications found

Variant links:

Genes affected

ERCC3 (HGNC:3435): (ERCC excision repair 3, TFIIH core complex helicase subunit) This gene encodes an ATP-dependent DNA helicase that functions in nucleotide excision repair. The encoded protein is a subunit of basal transcription factor 2 (TFIIH) and, therefore, also functions in class II transcription. Mutations in this gene are associated with Xeroderma pigmentosum B, Cockayne's syndrome, and trichothiodystrophy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ERCC3 Gene-Disease associations (from GenCC):

trichothiodystrophy 2, photosensitive
Inheritance: AR Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
xeroderma pigmentosum group B
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Genomics England PanelApp
trichothiodystrophy 1, photosensitive
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
trichothiodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
xeroderma pigmentosum
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
xeroderma pigmentosum-Cockayne syndrome complex
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ERCC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008400142).

BP6

Variant 2-127259402-G-A is Benign according to our data. Variant chr2-127259402-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 9 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC3	NM_000122.2 link	c.2111C>T	p.Ser704Leu	missense_variant	Exon 14 of 15	ENST00000285398.7	NP_000113.1	P19447

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC3	ENST00000285398.7 link	c.2111C>T	p.Ser704Leu	missense_variant	Exon 14 of 15	1	NM_000122.2	ENSP00000285398.2		P19447

Frequencies

GnomAD3 genomes

AF:

0.00224

AC:

341

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000580

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00400

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00622

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00267

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00220

AC:

552

AN:

251336

AF XY:

0.00215

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00292

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00702

Gnomad NFE exome

AF:

0.00210

Gnomad OTH exome

AF:

0.00505

GnomAD4 exome

AF:

0.00251

AC:

3675

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00238

AC XY:

1730

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33480

American (AMR)

AF:

0.00284

AC:

127

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000689

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000301

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00914

AC:

488

AN:

53418

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00256

AC:

2851

AN:

1112010

Other (OTH)

AF:

0.00242

AC:

146

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

241

481

722

962

1203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

106

212

318

424

530

<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:

0.00224

AC:

341

AN:

152240

Hom.:

Cov.:

AF XY:

0.00245

AC XY:

182

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.000578

AC:

AN:

41520

American (AMR)

AF:

0.00399

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00622

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00268

AC:

182

AN:

68030

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00215

Hom.:

Bravo

AF:

0.00175

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00217

AC:

264

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00191

EpiControl

AF:

0.00296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:2Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:4

Jan 08, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28259476, 27153395, 31346352, 30256826, 16550608, 30414346, 16574953, 24728327) -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ERCC3: BS2 -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ERCC3 p.Ser640Leu variant was not identified in the literature but was identified in dbSNP (ID: rs4150521) and ClinVar (classified as benign by Invitae; likely benign by Mendelics for Xeroderma pigmentosum, complementation group b and uncertain significance by CeGaT Praxis fuer Humangenetik Tuebingen). The variant was identified in control databases in 607 of 268178 chromosomes (2 homozygous) at a frequency of 0.002263 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 182 of 25100 chromosomes (freq: 0.007251), Other in 32 of 6702 chromosomes (freq: 0.004775), Latino in 103 of 35102 chromosomes (freq: 0.002934), European (non-Finnish) in 257 of 118038 chromosomes (freq: 0.002177), Ashkenazi Jewish in 12 of 9854 chromosomes (freq: 0.001218), African in 12 of 23604 chromosomes (freq: 0.000508) and South Asian in 9 of 30526 chromosomes (freq: 0.000295), but was not observed in the East Asian population. The p.Ser640 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Xeroderma pigmentosum group B

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Xeroderma pigmentosum

Benign:1

Jan 12, 2022

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

ERCC3-related disorder

Benign:1

Feb 25, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.0084

T;T

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.3

M;.

PhyloP100

5.3

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.3

D;.

REVEL

Benign

0.23

Sift

Benign

0.043

D;.

Sift4G

Uncertain

0.053

T;.

Polyphen

0.64

P;.

Vest4

0.27

MVP

0.85

MPC

0.32

ClinPred

0.022

GERP RS

5.5

Varity_R

0.27

gMVP

0.60

Mutation Taster

=74/26

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