rs4150342

Variant names:

Variant summary

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

The NM_000123.4(ERCC5):c.2636A>G(p.Asn879Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,614,222 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0093 ( 13 hom., cov: 32)

Exomes 𝑓: 0.012 ( 121 hom. )

Consequence

ERCC5
NM_000123.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 9.21

Publications

23 publications found

Variant links:

Genes affected

ERCC5 (HGNC:3437): (ERCC excision repair 5, endonuclease) This gene encodes a single-strand specific DNA endonuclease that makes the 3' incision in DNA excision repair following UV-induced damage. The protein may also function in other cellular processes, including RNA polymerase II transcription, and transcription-coupled DNA repair. Mutations in this gene cause xeroderma pigmentosum complementation group G (XP-G), which is also referred to as xeroderma pigmentosum VII (XP7), a skin disorder characterized by hypersensitivity to UV light and increased susceptibility for skin cancer development following UV exposure. Some patients also develop Cockayne syndrome, which is characterized by severe growth defects, cognitive disability, and cachexia. Read-through transcription exists between this gene and the neighboring upstream BIVM (basic, immunoglobulin-like variable motif containing) gene. [provided by RefSeq, Feb 2011]

ERCC5 links:

BIVM-ERCC5 (HGNC:43690): (BIVM-ERCC5 readthrough) This locus represents naturally occurring read-through transcription between the neighboring BIVM (basic, immunoglobulin-like variable motif containing) and ERCC5 (excision repair cross-complementing rodent repair deficiency, complementation group 5) genes on chromosome 13. The read-through transcript encodes a fusion protein that shares sequence identity with the products of each individual gene. [provided by RefSeq, Feb 2011]

BIVM-ERCC5 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=0.009051204).

BP6

Variant 13-102868215-A-G is Benign according to our data. Variant chr13-102868215-A-G is described in ClinVar as Benign. ClinVar VariationId is 134162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00933 (1422/152358) while in subpopulation AMR AF = 0.018 (276/15302). AF 95% confidence interval is 0.0163. There are 13 homozygotes in GnomAd4. There are 725 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC5	NM_000123.4 link	c.2636A>G	p.Asn879Ser	missense_variant	Exon 12 of 15	ENST00000652225.2	NP_000114.3
BIVM-ERCC5	NM_001204425.2 link	c.3998A>G	p.Asn1333Ser	missense_variant	Exon 20 of 23		NP_001191354.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ERCC5	ENST00000652225.2 link	c.2636A>G	p.Asn879Ser	missense_variant	Exon 12 of 15		NM_000123.4	ENSP00000498881.2
BIVM-ERCC5	ENST00000639435.1 link	c.3998A>G	p.Asn1333Ser	missense_variant	Exon 22 of 25	5		ENSP00000491742.1
BIVM-ERCC5	ENST00000639132.1 link	c.3311A>G	p.Asn1104Ser	missense_variant	Exon 21 of 24	5		ENSP00000492684.1

Frequencies

GnomAD3 genomes

AF:

0.00933

AC:

1421

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00236

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0181

Gnomad ASJ

AF:

0.00865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00475

Gnomad FIN

AF:

0.00828

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0129

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00987

AC:

2482

AN:

251464

AF XY:

0.00991

show subpopulations

Gnomad AFR exome

AF:

0.00215

Gnomad AMR exome

AF:

0.0106

Gnomad ASJ exome

AF:

0.00933

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00859

Gnomad NFE exome

AF:

0.0139

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.0118

AC:

17314

AN:

1461864

Hom.:

121

Cov.:

AF XY:

0.0117

AC XY:

8479

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00221

AC:

AN:

33480

American (AMR)

AF:

0.0115

AC:

515

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00980

AC:

256

AN:

26132

East Asian (EAS)

AF:

0.000151

AC:

AN:

39690

South Asian (SAS)

AF:

0.00460

AC:

397

AN:

86258

European-Finnish (FIN)

AF:

0.00760

AC:

406

AN:

53418

Middle Eastern (MID)

AF:

0.0191

AC:

110

AN:

5768

European-Non Finnish (NFE)

AF:

0.0134

AC:

14874

AN:

1112000

Other (OTH)

AF:

0.0112

AC:

676

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

930

1859

2789

3718

4648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

548

1096

1644

2192

2740

<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:

0.00933

AC:

1422

AN:

152358

Hom.:

Cov.:

AF XY:

0.00973

AC XY:

725

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.00236

AC:

AN:

41590

American (AMR)

AF:

0.0180

AC:

276

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00496

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00828

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0129

AC:

879

AN:

68036

Other (OTH)

AF:

0.0109

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

148

221

295

369

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:

0.00966

TwinsUK

AF:

0.0156

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.0140

AC:

120

ExAC

AF:

0.00951

AC:

1155

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0133

EpiControl

AF:

0.0151

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

May 29, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 11841555, 24728327) -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ERCC5 p.Asn879Ser variant was identified in dbSNP (ID: rs4150342) and ClinVar (submitted by ITMI with no classification) but was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 2751 of 282866 chromosomes (15 homozygous) at a frequency of 0.009725 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 1776 of 129182 chromosomes (freq: 0.01375), Latino in 384 of 35438 chromosomes (freq: 0.01084), Other in 77 of 7224 chromosomes (freq: 0.01066), Ashkenazi Jewish in 95 of 10370 chromosomes (freq: 0.009161), European (Finnish) in 218 of 25122 chromosomes (freq: 0.008678), South Asian in 143 of 30616 chromosomes (freq: 0.004671), African in 56 of 24964 chromosomes (freq: 0.002243), and East Asian in 2 of 19950 chromosomes (freq: 0.0001). The variant was identified in a patient with Xeroderma Pigmentosum who also carried multiple other ERCC5 variants, therefore the N879S variant was not expected to have functional significance (Lalle_2002_PMID:11841555). The p.Asn879 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ERCC5: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Xeroderma pigmentosum, group G

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

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

0.21

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

.;.;.;T;.

Eigen

Benign

-0.013

Eigen_PC

Benign

0.17

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;.;D;D

MetaRNN

Benign

0.0091

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

.;.;.;L;.

PhyloP100

9.2

PROVEAN

Uncertain

-2.6

.;.;.;D;N

REVEL

Benign

0.23

Sift

Benign

0.32

.;.;.;T;T

Sift4G

Benign

0.28

.;.;.;T;T

Polyphen

0.52

.;.;.;P;.

Vest4

0.59, 0.67

MVP

0.66

MPC

0.50

ClinPred

0.021

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.40

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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