chr13-102846025-T-C

Variant names:

• chr13-102846025-T-C
• rs2296147
• ENST00000639435.1:c.1451-6093T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000639435.1(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 ENST00000639435.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.260
• Publications: 91 publications found

Genes affected

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: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]

ERCC5 Gene-Disease associations (from GenCC):

• xeroderma pigmentosum group G

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• cerebrooculofacioskeletal syndrome 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• COFS syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum-Cockayne syndrome complex

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000305730 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000639435.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIVM-ERCC5	NM_001204425.2		c.1451-6093T>C		intron	N/A	NP_001191354.2
	ERCC5	NM_000123.4	MANE Select	c.-242T>C		upstream_gene	N/A	NP_000114.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIVM-ERCC5	ENST00000639435.1	TSL:5	c.1451-6093T>C		intron	N/A	ENSP00000491742.1
	BIVM-ERCC5	ENST00000639132.1	TSL:5	c.764-6093T>C		intron	N/A	ENSP00000492684.1
	ERCC5	ENST00000535557.5	TSL:5	n.185T>C		non_coding_transcript_exon	Exon 1 of 7

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

African (AFR) AF: 0.201 AC: 2348 AN: 11664

American (AMR) AF: 0.281 AC: 4558 AN: 16224

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 6075 AN: 12802

East Asian (EAS) AF: 0.151 AC: 4467 AN: 29670

South Asian (SAS) AF: 0.441 AC: 17054 AN: 38654

European-Finnish (FIN) AF: 0.413 AC: 11321 AN: 27436

Middle Eastern (MID) AF: 0.444 AC: 817 AN: 1842

European-Non Finnish (NFE) AF: 0.480 AC: 118066 AN: 245854

Other (OTH) AF: 0.423 AC: 10170 AN: 24036

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

African (AFR) AF: 0.208 AC: 8633 AN: 41546

American (AMR) AF: 0.334 AC: 5099 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 1760 AN: 3472

East Asian (EAS) AF: 0.183 AC: 950 AN: 5186

South Asian (SAS) AF: 0.428 AC: 2067 AN: 4826

European-Finnish (FIN) AF: 0.420 AC: 4447 AN: 10584

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.482 AC: 32765 AN: 67994

Other (OTH) AF: 0.397 AC: 840 AN: 2116

Alfa AF: 0.434 Hom.: 41534

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

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Xeroderma pigmentosum, group G Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.9
DANN	Benign	0.55
PhyloP100		-0.26
PromoterAI		0.099	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

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