rs1047769

chr13-102861594-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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 2.92

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:):

ACMG classification

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	UniProt
ERCC5	NM_000123.4	c.760A>G	p.Met254Val	missense_variant	7/15	ENST00000652225.2
BIVM-ERCC5	NM_001204425.2	c.2122A>G	p.Met708Val	missense_variant	15/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC5	ENST00000652225.2	c.760A>G	p.Met254Val	missense_variant	7/15		NM_000123.4	P1

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 3870 AN: 152230 Hom.: 61 Cov.: 32

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

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.: 31 AF XY: 0.0359 AC XY: 26125 AN XY: 727224

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.: 61 Cov.: 32 AF XY: 0.0251 AC XY: 1868 AN XY: 74494

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: 39

ESP6500EA AF: 0.0359 AC: 309

ExAC AF: 0.0294 AC: 3564

Asia WGS AF: 0.0200 AC: 71 AN: 3478

EpiCase AF: 0.0431

EpiControl AF: 0.0442

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum, group G Benign:3

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. -
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	- -

not specified Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D;.;D
MetaRNN	Benign	0.0047	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
Polyphen		0.86	.;.;.;P
Vest4		0.22
MPC		0.38
ClinPred		0.031	T
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

Other links and lift over

dbSNP: rs1047769; hg19: chr13-103513944; COSMIC: COSV63244772; COSMIC: COSV63244772;