chr13-102862735-G-C

Position:

• chr13-102862735-G-C

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.1586G>C​(p.Cys529Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0401 in 1,614,202 control chromosomes in the GnomAD database, including 1,412 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (161 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1251 hom.)
• Consequence: ERCC5 NM_000123.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:8 O:1
• Conservation: PhyloP100: 0.247

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=0.0019605458).
• BP6: Variant 13-102862735-G-C is Benign according to our data. Variant chr13-102862735-G-C is described in ClinVar as [Benign]. Clinvar id is 129010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-102862735-G-C is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC5	NM_000123.4	c.1586G>C	p.Cys529Ser	missense_variant	8/15	ENST00000652225.2	NP_000114.3
BIVM-ERCC5	NM_001204425.2	c.2948G>C	p.Cys983Ser	missense_variant	16/23		NP_001191354.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC5	ENST00000652225.2	c.1586G>C	p.Cys529Ser	missense_variant	8/15		NM_000123.4	ENSP00000498881	P1

Frequencies

GnomAD3 genomes AF: 0.0437 AC: 6648 AN: 152204 Hom.: 162 Cov.: 32

Gnomad AFR AF: 0.0418

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0297

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.0450

Gnomad SAS AF: 0.0471

Gnomad FIN AF: 0.0683

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0446

Gnomad OTH AF: 0.0531

GnomAD3 exomes AF: 0.0426 AC: 10707 AN: 251362 Hom.: 267 AF XY: 0.0434 AC XY: 5895 AN XY: 135854

Gnomad AFR exome AF: 0.0407

Gnomad AMR exome AF: 0.0217

Gnomad ASJ exome AF: 0.0349

Gnomad EAS exome AF: 0.0455

Gnomad SAS exome AF: 0.0452

Gnomad FIN exome AF: 0.0694

Gnomad NFE exome AF: 0.0434

Gnomad OTH exome AF: 0.0463

GnomAD4 exome AF: 0.0398 AC: 58133 AN: 1461880 Hom.: 1251 Cov.: 32 AF XY: 0.0401 AC XY: 29180 AN XY: 727240

Gnomad4 AFR exome AF: 0.0442

Gnomad4 AMR exome AF: 0.0231

Gnomad4 ASJ exome AF: 0.0369

Gnomad4 EAS exome AF: 0.0517

Gnomad4 SAS exome AF: 0.0443

Gnomad4 FIN exome AF: 0.0667

Gnomad4 NFE exome AF: 0.0380

Gnomad4 OTH exome AF: 0.0420

GnomAD4 genome AF: 0.0437 AC: 6656 AN: 152322 Hom.: 161 Cov.: 32 AF XY: 0.0444 AC XY: 3307 AN XY: 74484

Gnomad4 AFR AF: 0.0419

Gnomad4 AMR AF: 0.0297

Gnomad4 ASJ AF: 0.0297

Gnomad4 EAS AF: 0.0451

Gnomad4 SAS AF: 0.0476

Gnomad4 FIN AF: 0.0683

Gnomad4 NFE AF: 0.0446

Gnomad4 OTH AF: 0.0521

Alfa AF: 0.0430 Hom.: 123

Bravo AF: 0.0395

TwinsUK AF: 0.0343 AC: 127

ALSPAC AF: 0.0374 AC: 144

ESP6500AA AF: 0.0433 AC: 191

ESP6500EA AF: 0.0431 AC: 371

ExAC AF: 0.0441 AC: 5357

Asia WGS AF: 0.0460 AC: 160 AN: 3478

EpiCase AF: 0.0400

EpiControl AF: 0.0406

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Xeroderma pigmentosum, group G Benign:3

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, 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	Jan 22, 2016	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.16
DANN	Benign	0.20
DEOGEN2	Benign	0.036	.;.;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.32	T;T;.;T
MetaRNN	Benign	0.0020	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.8	.;.;.;N
MutationTaster	Benign	1.0	N
PROVEAN	Benign	1.0	.;.;.;N
REVEL	Benign	0.023
Sift	Benign	0.88	.;.;.;T
Sift4G	Benign	0.79	.;.;.;T
Polyphen		0.0	.;.;.;B
Vest4		0.0030
MutPred		0.36		.;.;.;Gain of glycosylation at C529 (P = 0.0043);
MPC		0.14
ClinPred		0.0026	T
GERP RS		1.9
Varity_R		0.025
gMVP		0.28

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: rs2227869; hg19: chr13-103515085; COSMIC: COSV63243735; COSMIC: COSV63243735;