rs4150313

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000123.4(ERCC5):c.767A>G(p.Gln256Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0062 in 1,614,178 control chromosomes in the GnomAD database, including 277 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 115 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 162 hom. )

Consequence

ERCC5
NM_000123.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.86

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022942126).

BP6

Variant 13-102861601-A-G is Benign according to our data. Variant chr13-102861601-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 134182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-102861601-A-G is described in Lovd as [Benign]. Variant chr13-102861601-A-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0752 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC5	NM_000123.4 link	c.767A>G	p.Gln256Arg	missense_variant	Exon 7 of 15	ENST00000652225.2	NP_000114.3	P28715-1
BIVM-ERCC5	NM_001204425.2 link	c.2129A>G	p.Gln710Arg	missense_variant	Exon 15 of 23		NP_001191354.2	R4GMW8Q59FZ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ERCC5	ENST00000652225.2 link	c.767A>G	p.Gln256Arg	missense_variant	Exon 7 of 15		NM_000123.4	ENSP00000498881.2	P28715-1
BIVM-ERCC5	ENST00000639435.1 link	c.2129A>G	p.Gln710Arg	missense_variant	Exon 17 of 25	5		ENSP00000491742.1	R4GMW8
BIVM-ERCC5	ENST00000639132.1 link	c.1442A>G	p.Gln481Arg	missense_variant	Exon 16 of 24	5		ENSP00000492684.1	A0A1W2PS85

Frequencies

GnomAD3 genomes

AF:

0.0241

AC:

3673

AN:

152204

Hom.:

115

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0775

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0113

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.0164

Gnomad SAS

AF:

0.0139

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00106

Gnomad OTH

AF:

0.0167

GnomAD3 exomes

AF:

0.00998

AC:

2509

AN:

251384

Hom.:

AF XY:

0.00902

AC XY:

1225

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.0792

Gnomad AMR exome

AF:

0.00532

Gnomad ASJ exome

AF:

0.000893

Gnomad EAS exome

AF:

0.0185

Gnomad SAS exome

AF:

0.0146

Gnomad FIN exome

AF:

0.00152

Gnomad NFE exome

AF:

0.00143

Gnomad OTH exome

AF:

0.00702

GnomAD4 exome

AF:

0.00433

AC:

6323

AN:

1461856

Hom.:

162

Cov.:

AF XY:

0.00436

AC XY:

3171

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0801

Gnomad4 AMR exome

AF:

0.00595

Gnomad4 ASJ exome

AF:

0.00115

Gnomad4 EAS exome

AF:

0.0117

Gnomad4 SAS exome

AF:

0.0153

Gnomad4 FIN exome

AF:

0.00187

Gnomad4 NFE exome

AF:

0.000835

Gnomad4 OTH exome

AF:

0.00796

GnomAD4 genome

AF:

0.0241

AC:

3678

AN:

152322

Hom.:

115

Cov.:

AF XY:

0.0238

AC XY:

1772

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0774

Gnomad4 AMR

AF:

0.0112

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.0164

Gnomad4 SAS

AF:

0.0139

Gnomad4 FIN

AF:

0.00188

Gnomad4 NFE

AF:

0.00106

Gnomad4 OTH

AF:

0.0170

Alfa

AF:

0.00635

Hom.:

Bravo

AF:

0.0271

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.0726

AC:

320

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.0118

AC:

1430

Asia WGS

AF:

0.0210

AC:

AN:

3478

EpiCase

AF:

0.00207

EpiControl

AF:

0.00237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Xeroderma pigmentosum, group G

Benign:4

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 08, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 21, 2015

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 03, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

ERCC5-related disorder

Benign:1

Sep 25, 2019

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

0.11

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

.;.;.;T

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

D;D;.;D

MetaRNN

Benign

0.0023

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

.;.;.;L

PROVEAN

Uncertain

-2.6

.;.;.;D

REVEL

Benign

0.13

Sift

Uncertain

0.012

.;.;.;D

Sift4G

Benign

0.24

.;.;.;T

Polyphen

1.0

.;.;.;D

Vest4

0.074

MPC

0.57

ClinPred

0.038

GERP RS

5.6

Varity_R

0.35

gMVP

0.098

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over