rs4150314

Positions:

• chr13-102862109-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000123.4(ERCC5):​c.960C>T​(p.Asp320Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,614,120 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (13 hom., cov: 33)
  • Exomes 𝑓: 0.012 (118 hom.)
• Consequence: ERCC5 NM_000123.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.375

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 13-102862109-C-T is Benign according to our data. Variant chr13-102862109-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 522357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-102862109-C-T is described in Lovd as [Benign]. Variant chr13-102862109-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.375 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00928 (1413/152232) while in subpopulation AMR AF= 0.018 (276/15296). AF 95% confidence interval is 0.0163. There are 13 homozygotes in gnomad4. There are 721 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC5	NM_000123.4	c.960C>T	p.Asp320Asp	synonymous_variant	8/15	ENST00000652225.2	NP_000114.3
BIVM-ERCC5	NM_001204425.2	c.2322C>T	p.Asp774Asp	synonymous_variant	16/23		NP_001191354.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC5	ENST00000652225.2	c.960C>T	p.Asp320Asp	synonymous_variant	8/15		NM_000123.4	ENSP00000498881.2
BIVM-ERCC5	ENST00000639435.1	c.2322C>T	p.Asp774Asp	synonymous_variant	18/25	5		ENSP00000491742.1
BIVM-ERCC5	ENST00000639132.1	c.1635C>T	p.Asp545Asp	synonymous_variant	17/24	5		ENSP00000492684.1

Frequencies

GnomAD3 genomes AF: 0.00928 AC: 1412 AN: 152114 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00840

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.0106

GnomAD3 exomes AF: 0.00986 AC: 2478 AN: 251272 Hom.: 13 AF XY: 0.00989 AC XY: 1343 AN XY: 135828

Gnomad AFR exome AF: 0.00222

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.00933

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00467

Gnomad FIN exome AF: 0.00859

Gnomad NFE exome AF: 0.0139

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0118 AC: 17244 AN: 1461888 Hom.: 118 Cov.: 32 AF XY: 0.0116 AC XY: 8436 AN XY: 727248

Gnomad4 AFR exome AF: 0.00215

Gnomad4 AMR exome AF: 0.0114

Gnomad4 ASJ exome AF: 0.00979

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00458

Gnomad4 FIN exome AF: 0.00760

Gnomad4 NFE exome AF: 0.0133

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.00928 AC: 1413 AN: 152232 Hom.: 13 Cov.: 33 AF XY: 0.00969 AC XY: 721 AN XY: 74434

Gnomad4 AFR AF: 0.00226

Gnomad4 AMR AF: 0.0180

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.00840

Gnomad4 NFE AF: 0.0129

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0126 Hom.: 15

Bravo AF: 0.00960

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0150

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	BIVM-ERCC5: BP4, BP7, BS1, BS2; ERCC5: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2020	- -

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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Aug 07, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.5
DANN	Benign	0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs4150314; hg19: chr13-103514459; COSMIC: COSV104673101; COSMIC: COSV104673101;