rs1047769

Positions:

chr13-102861594-A-G

Variant summary

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

The NM_000123.4(ERCC5):c.760A>G(p.Met254Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0342 in 1,614,194 control chromosomes in the GnomAD database, including 1,108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 61 hom., cov: 32)

Exomes 𝑓: 0.035 ( 1047 hom. )

Consequence

ERCC5
NM_000123.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.92

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:

ERCC5 (HGNC:):

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=0.0047145486).

BP6

Variant 13-102861594-A-G is Benign according to our data. Variant chr13-102861594-A-G is described in ClinVar as [Benign]. Clinvar id is 129012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-102861594-A-G is described in Lovd as [Benign]. Variant chr13-102861594-A-G is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC5	NM_000123.4 linkuse as main transcript	c.760A>G	p.Met254Val	missense_variant	7/15	ENST00000652225.2	NP_000114.3	P28715-1
BIVM-ERCC5	NM_001204425.2 linkuse as main transcript	c.2122A>G	p.Met708Val	missense_variant	15/23		NP_001191354.2	R4GMW8Q59FZ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ERCC5	ENST00000652225.2 linkuse as main transcript	c.760A>G	p.Met254Val	missense_variant	7/15		NM_000123.4	ENSP00000498881.2	P28715-1
BIVM-ERCC5	ENST00000639435.1 linkuse as main transcript	c.2122A>G	p.Met708Val	missense_variant	17/25	5		ENSP00000491742.1	R4GMW8
BIVM-ERCC5	ENST00000639132.1 linkuse as main transcript	c.1435A>G	p.Met479Val	missense_variant	16/24	5		ENSP00000492684.1	A0A1W2PS85

Frequencies

GnomAD3 genomes

AF:

0.0254

AC:

3870

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00726

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.0275

Gnomad ASJ

AF:

0.0541

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0399

Gnomad FIN

AF:

0.0168

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0362

Gnomad OTH

AF:

0.0383

GnomAD3 exomes

AF:

0.0299

AC:

7516

AN:

251364

Hom.:

163

AF XY:

0.0330

AC XY:

4481

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.00640

Gnomad AMR exome

AF:

0.0186

Gnomad ASJ exome

AF:

0.0602

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.0450

Gnomad FIN exome

AF:

0.0134

Gnomad NFE exome

AF:

0.0375

Gnomad OTH exome

AF:

0.0369

GnomAD4 exome

AF:

0.0352

AC:

51401

AN:

1461846

Hom.:

1047

Cov.:

AF XY:

0.0359

AC XY:

26125

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00573

Gnomad4 AMR exome

AF:

0.0190

Gnomad4 ASJ exome

AF:

0.0604

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0464

Gnomad4 FIN exome

AF:

0.0130

Gnomad4 NFE exome

AF:

0.0374

Gnomad4 OTH exome

AF:

0.0343

GnomAD4 genome

AF:

0.0254

AC:

3871

AN:

152348

Hom.:

Cov.:

AF XY:

0.0251

AC XY:

1868

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00724

Gnomad4 AMR

AF:

0.0274

Gnomad4 ASJ

AF:

0.0541

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0406

Gnomad4 FIN

AF:

0.0168

Gnomad4 NFE

AF:

0.0361

Gnomad4 OTH

AF:

0.0379

Alfa

AF:

0.0370

Hom.:

275

Bravo

AF:

0.0259

TwinsUK

AF:

0.0318

AC:

118

ALSPAC

AF:

0.0449

AC:

173

ESP6500AA

AF:

0.00885

AC:

ESP6500EA

AF:

0.0359

AC:

309

ExAC

AF:

0.0294

AC:

3564

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0431

EpiControl

AF:

0.0442

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Xeroderma pigmentosum, group G

Benign:3

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	May 08, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2Other:1

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

.;.;.;T

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

D;D;.;D

MetaRNN

Benign

0.0047

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

.;.;.;M

PROVEAN

Uncertain

-3.4

.;.;.;D

REVEL

Benign

0.10

Sift

Uncertain

0.026

.;.;.;D

Sift4G

Uncertain

0.012

.;.;.;D

Polyphen

0.86

.;.;.;P

Vest4

0.22

MPC

0.38

ClinPred

0.031

GERP RS

5.6

Varity_R

0.30

gMVP

0.36

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