rs1047768

Positions:

• chr13-102852167-T-C
• chr13-102852167-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000123.4(ERCC5):​c.138T>C​(p.His46=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 1,613,696 control chromosomes in the GnomAD database, including 273,288 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26664 hom., cov: 32)
  • Exomes 𝑓: 0.57 (246624 hom.)
• Consequence: ERCC5 NM_000123.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.00400

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 13-102852167-T-C is Benign according to our data. Variant chr13-102852167-T-C is described in ClinVar as [Benign]. Clinvar id is 129009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-102852167-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.004 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC5	NM_000123.4	c.138T>C	p.His46=	synonymous_variant	2/15	ENST00000652225.2
BIVM-ERCC5	NM_001204425.2	c.1500T>C	p.His500=	synonymous_variant	10/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC5	ENST00000652225.2	c.138T>C	p.His46=	synonymous_variant	2/15		NM_000123.4	P1

Frequencies

GnomAD3 genomes AF: 0.583 AC: 88613 AN: 151876 Hom.: 26615 Cov.: 32

Gnomad AFR AF: 0.665

Gnomad AMI AF: 0.581

Gnomad AMR AF: 0.426

Gnomad ASJ AF: 0.590

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.623

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.596

Gnomad OTH AF: 0.568

GnomAD3 exomes AF: 0.520 AC: 130641 AN: 251366 Hom.: 36398 AF XY: 0.527 AC XY: 71638 AN XY: 135852

Gnomad AFR exome AF: 0.662

Gnomad AMR exome AF: 0.295

Gnomad ASJ exome AF: 0.576

Gnomad EAS exome AF: 0.264

Gnomad SAS exome AF: 0.498

Gnomad FIN exome AF: 0.619

Gnomad NFE exome AF: 0.590

Gnomad OTH exome AF: 0.546

GnomAD4 exome AF: 0.574 AC: 839091 AN: 1461702 Hom.: 246624 Cov.: 56 AF XY: 0.573 AC XY: 416387 AN XY: 727164

Gnomad4 AFR exome AF: 0.668

Gnomad4 AMR exome AF: 0.310

Gnomad4 ASJ exome AF: 0.577

Gnomad4 EAS exome AF: 0.224

Gnomad4 SAS exome AF: 0.501

Gnomad4 FIN exome AF: 0.613

Gnomad4 NFE exome AF: 0.599

Gnomad4 OTH exome AF: 0.566

GnomAD4 genome AF: 0.584 AC: 88713 AN: 151994 Hom.: 26664 Cov.: 32 AF XY: 0.580 AC XY: 43078 AN XY: 74280

Gnomad4 AFR AF: 0.665

Gnomad4 AMR AF: 0.426

Gnomad4 ASJ AF: 0.590

Gnomad4 EAS AF: 0.249

Gnomad4 SAS AF: 0.495

Gnomad4 FIN AF: 0.623

Gnomad4 NFE AF: 0.596

Gnomad4 OTH AF: 0.571

Alfa AF: 0.578 Hom.: 50731

Bravo AF: 0.569

Asia WGS AF: 0.406 AC: 1415 AN: 3478

EpiCase AF: 0.584

EpiControl AF: 0.586

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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	-	- -

Xeroderma pigmentosum, group G Benign:2

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	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.10
DANN	Benign	0.33

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: rs1047768; hg19: chr13-103504517; COSMIC: COSV63245576;