rs752661599

Positions:

• chr13-102872261-GA-G
• chr13-102872261-GA-GAA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000123.4(ERCC5):​c.2751del​(p.Lys917AsnfsTer65) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,272 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ERCC5 NM_000123.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.25

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-102872261-GA-G is Pathogenic according to our data. Variant chr13-102872261-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 16576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC5	NM_000123.4	c.2751del	p.Lys917AsnfsTer65	frameshift_variant	13/15	ENST00000652225.2	NP_000114.3
BIVM-ERCC5	NM_001204425.2	c.4113del	p.Lys1371AsnfsTer65	frameshift_variant	21/23		NP_001191354.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC5	ENST00000652225.2	c.2751del	p.Lys917AsnfsTer65	frameshift_variant	13/15		NM_000123.4	ENSP00000498881	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461272 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726952

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum, group G Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The frameshift variant c.2751del (p.Lys917AsnfsTer65) in the ERCC5 gene has been reported previously in a heterozygous state in individuals affected with xeroderma pigmentosum (Drury et al., 2014; Lalle et al., 2022). The p.Lys917AsnfsTer65 variant is absent in 1000 Genomes. It has been submitted to ClinVar as Pathogenic. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

Xeroderma pigmentosum Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 21, 2019

Variant summary: ERCC5 c.2751delA (p.Lys917AsnfsX65) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 248226 control chromosomes (gnomAD). c.2751delA has been reported in the literature in a compound heterozygous individual affected with Xeroderma pigmentosum (Lalle_2002). These data indicate that the variant is likely to be associated with disease. In functional studies, the cells transfected with the variant were highly UV sensitive compared to control cells (Lalle_2002).No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2023

Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. For these reasons, this variant has been classified as Pathogenic. Studies have shown that this premature translational stop signal is associated with altered splicing resulting in multiple RNA products (PMID: 11841555). Experimental studies have shown that this premature translational stop signal affects ERCC5 function (PMID: 11841555). ClinVar contains an entry for this variant (Variation ID: 16576). This variant is also known as K917fs962fsX1186. This premature translational stop signal has been observed in individuals with clinical features of xeroderma pigmentosum (PMID: 11841555; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys917Asnfs*65) in the ERCC5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 270 amino acid(s) of the ERCC5 protein. -

Computational scores

Source: dbNSFP v4.3

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: rs752661599; hg19: chr13-103524611;