rs2296147

Positions:

• chr13-102846025-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001204425.2(BIVM-ERCC5):​c.1451-6093T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 560,396 control chromosomes in the GnomAD database, including 51,789 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11961 hom., cov: 33)
  • Exomes 𝑓: 0.43 (39828 hom.)
• Consequence: BIVM-ERCC5 NM_001204425.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.260

Genes affected

BIVM-ERCC5 (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 13-102846025-T-C is Benign according to our data. Variant chr13-102846025-T-C is described in ClinVar as [Benign]. Clinvar id is 310904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.478 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BIVM-ERCC5	NM_001204425.2	c.1451-6093T>C		intron_variant			NP_001191354.2
ERCC5	NM_000123.4			upstream_gene_variant		ENST00000652225.2	NP_000114.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC5	ENST00000652225.2			upstream_gene_variant			NM_000123.4	ENSP00000498881	P1

Frequencies

GnomAD3 genomes AF: 0.376 AC: 57113 AN: 152096 Hom.: 11941 Cov.: 33

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.534

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.420

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.482

Gnomad OTH AF: 0.391

GnomAD4 exome AF: 0.428 AC: 174876 AN: 408182 Hom.: 39828 Cov.: 2 AF XY: 0.432 AC XY: 92355 AN XY: 213878

Gnomad4 AFR exome AF: 0.201

Gnomad4 AMR exome AF: 0.281

Gnomad4 ASJ exome AF: 0.475

Gnomad4 EAS exome AF: 0.151

Gnomad4 SAS exome AF: 0.441

Gnomad4 FIN exome AF: 0.413

Gnomad4 NFE exome AF: 0.480

Gnomad4 OTH exome AF: 0.423

GnomAD4 genome AF: 0.376 AC: 57158 AN: 152214 Hom.: 11961 Cov.: 33 AF XY: 0.374 AC XY: 27810 AN XY: 74426

Gnomad4 AFR AF: 0.208

Gnomad4 AMR AF: 0.334

Gnomad4 ASJ AF: 0.507

Gnomad4 EAS AF: 0.183

Gnomad4 SAS AF: 0.428

Gnomad4 FIN AF: 0.420

Gnomad4 NFE AF: 0.482

Gnomad4 OTH AF: 0.397

Alfa AF: 0.454 Hom.: 27652

Bravo AF: 0.357

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

Xeroderma pigmentosum, group G Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.9
DANN	Benign	0.55

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: rs2296147; hg19: chr13-103498375; COSMIC: COSV57281060; COSMIC: COSV57281060;