rs4150313

chr13-102861601-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 6.86

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]

BIVM-ERCC5 (HGNC:):

ACMG classification

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/exons	MANE	UniProt
ERCC5	NM_000123.4	c.767A>G	p.Gln256Arg	missense_variant	7/15	ENST00000652225.2
BIVM-ERCC5	NM_001204425.2	c.2129A>G	p.Gln710Arg	missense_variant	15/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC5	ENST00000652225.2	c.767A>G	p.Gln256Arg	missense_variant	7/15		NM_000123.4	P1

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3673 AN: 152204 Hom.: 115 Cov.: 32

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.: 72 AF XY: 0.00902 AC XY: 1225 AN XY: 135854

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.: 31 AF XY: 0.00436 AC XY: 3171 AN XY: 727230

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.: 32 AF XY: 0.0238 AC XY: 1772 AN XY: 74484

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.: 66

Bravo AF: 0.0271

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.0726 AC: 320

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.0118 AC: 1430

Asia WGS AF: 0.0210 AC: 73 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum, group G Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jul 08, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

ERCC5-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2019

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

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.45
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D;.;D
MetaRNN	Benign	0.0023	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
Polyphen		1.0	.;.;.;D
Vest4		0.074
MPC		0.57
ClinPred		0.038	T
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

Other links and lift over

dbSNP: rs4150313; hg19: chr13-103513951; COSMIC: COSV104673111; COSMIC: COSV104673111;