chr13-102863029-C-A

Position:

• chr13-102863029-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000123.4(ERCC5):​c.1880C>A​(p.Ala627Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,614,156 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (61 hom.)
• Consequence: ERCC5 NM_000123.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.966

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003184855).
• BP6: Variant 13-102863029-C-A is Benign according to our data. Variant chr13-102863029-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 134192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00338 (514/152278) while in subpopulation AMR AF= 0.0191 (292/15304). AF 95% confidence interval is 0.0173. There are 3 homozygotes in gnomad4. There are 301 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC5	NM_000123.4	c.1880C>A	p.Ala627Glu	missense_variant	8/15	ENST00000652225.2	NP_000114.3
BIVM-ERCC5	NM_001204425.2	c.3242C>A	p.Ala1081Glu	missense_variant	16/23		NP_001191354.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC5	ENST00000652225.2	c.1880C>A	p.Ala627Glu	missense_variant	8/15		NM_000123.4	ENSP00000498881.2
BIVM-ERCC5	ENST00000639435.1	c.3242C>A	p.Ala1081Glu	missense_variant	18/25	5		ENSP00000491742.1
BIVM-ERCC5	ENST00000639132.1	c.2555C>A	p.Ala852Glu	missense_variant	17/24	5		ENSP00000492684.1

Frequencies

GnomAD3 genomes AF: 0.00336 AC: 512 AN: 152160 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0190

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00782 AC: 1965 AN: 251264 Hom.: 53 AF XY: 0.00603 AC XY: 819 AN XY: 135802

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0456

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00125

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.000387

Gnomad OTH exome AF: 0.00621

GnomAD4 exome AF: 0.00198 AC: 2890 AN: 1461878 Hom.: 61 Cov.: 32 AF XY: 0.00174 AC XY: 1263 AN XY: 727238

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0423

Gnomad4 ASJ exome AF: 0.000765

Gnomad4 EAS exome AF: 0.00116

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.0121

Gnomad4 NFE exome AF: 0.000123

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00338 AC: 514 AN: 152278 Hom.: 3 Cov.: 32 AF XY: 0.00404 AC XY: 301 AN XY: 74460

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.0191

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00290

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0127

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000558 Hom.: 1

Bravo AF: 0.00459

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00605 AC: 735

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -

Xeroderma pigmentosum, group G Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Benign	0.073	.;.;.;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.71	T;T;.;T
MetaRNN	Benign	0.0032	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	.;.;.;M
PROVEAN	Benign	-1.6	.;.;.;N
REVEL	Benign	0.037
Sift	Benign	0.10	.;.;.;T
Sift4G	Benign	0.50	.;.;.;T
Polyphen		0.65	.;.;.;P
Vest4		0.18
MVP		0.38
MPC		0.28
ClinPred		0.022	T
GERP RS		3.6
Varity_R		0.13
gMVP		0.32

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: rs2227870; hg19: chr13-103515379; COSMIC: COSV63244005; COSMIC: COSV63244005;