rs146344855

Positions:

• chr13-102872337-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000123.4(ERCC5):​c.2818G>A​(p.Val940Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,614,138 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: ERCC5 NM_000123.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:7
• Conservation: PhyloP100: 1.92

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: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]

ERCC5 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012758315).
• BP6: Variant 13-102872337-G-A is Benign according to our data. Variant chr13-102872337-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 310936.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC5	NM_000123.4	c.2818G>A	p.Val940Met	missense_variant	13/15	ENST00000652225.2	NP_000114.3
BIVM-ERCC5	NM_001204425.2	c.4180G>A	p.Val1394Met	missense_variant	21/23		NP_001191354.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC5	ENST00000652225.2	c.2818G>A	p.Val940Met	missense_variant	13/15		NM_000123.4	ENSP00000498881.2
BIVM-ERCC5	ENST00000639435.1	c.4180G>A	p.Val1394Met	missense_variant	23/25	5		ENSP00000491742.1
BIVM-ERCC5	ENST00000639132.1	c.3493G>A	p.Val1165Met	missense_variant	22/24	5		ENSP00000492684.1

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 167 AN: 152128 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000883 AC: 222 AN: 251474 Hom.: 1 AF XY: 0.000927 AC XY: 126 AN XY: 135912

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00506

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00130 AC: 1905 AN: 1461892 Hom.: 1 Cov.: 31 AF XY: 0.00124 AC XY: 900 AN XY: 727248

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00543

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.00147

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.00110 AC: 167 AN: 152246 Hom.: 1 Cov.: 32 AF XY: 0.000940 AC XY: 70 AN XY: 74448

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00147

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00161 Hom.: 1

Bravo AF: 0.00119

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000824 AC: 100

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	ERCC5: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2022	See Variant Classification Assertion Criteria. -

Xeroderma pigmentosum, group G Uncertain:2 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 08, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 01, 2017	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. -

Xeroderma pigmentosum, group G;C1851443:Cerebrooculofacioskeletal syndrome 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 21, 2023

Variant summary: ERCC5 c.2818G>A (p.Val940Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00088 in 251474 control chromosomes, including 1 homozygote, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. To our knowledge, no occurrence of c.2818G>A in individuals affected with Cerebrooculofacioskeletal Syndrome 3 and no experimental evidence demonstrating its impact on protein function have been reported. Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as likely benign (n=6) or uncertain significance (n=4). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

May 10, 2021

- -

BIVM-ERCC5-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2020

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	.;.;.;T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D;D;.;D;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.013	T;T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	2.0	.;.;.;M;.
PROVEAN	Benign	-1.6	.;.;.;N;N
REVEL	Benign	0.19
Sift	Benign	0.035	.;.;.;D;T
Sift4G	Benign	0.070	.;.;.;T;T
Polyphen		1.0	.;.;.;D;.
Vest4		0.37, 0.39
MVP		0.71
MPC		0.54
ClinPred		0.037	T
GERP RS		5.5
Varity_R		0.25
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs146344855; hg19: chr13-103524687; COSMIC: COSV99053839; COSMIC: COSV99053839;