rs751402

chr13-102845848-A-G

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.1450+6045A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.764 in 258,432 control chromosomes in the GnomAD database, including 76,284 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (43735 hom., cov: 34)
  • Exomes 𝑓: 0.78 (32549 hom.)
• Consequence: BIVM-ERCC5 NM_001204425.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.57

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=-0.78).
• BP6: Variant 13-102845848-A-G is Benign according to our data. Variant chr13-102845848-A-G is described in ClinVar as [Benign]. Clinvar id is 310903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BIVM-ERCC5	NM_001204425.2	c.1450+6045A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC5	ENST00000535557.5	n.8A>G		non_coding_transcript_exon_variant	1/7	5
ERCC5	ENST00000651002.1	c.-419A>G		5_prime_UTR_variant, NMD_transcript_variant	1/15
ERCC5	ENST00000652613.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.755 AC: 114866 AN: 152044 Hom.: 43702 Cov.: 34

Gnomad AFR AF: 0.687

Gnomad AMI AF: 0.815

Gnomad AMR AF: 0.682

Gnomad ASJ AF: 0.860

Gnomad EAS AF: 0.626

Gnomad SAS AF: 0.714

Gnomad FIN AF: 0.797

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.814

Gnomad OTH AF: 0.762

GnomAD4 exome AF: 0.777 AC: 82596 AN: 106270 Hom.: 32549 Cov.: 0 AF XY: 0.779 AC XY: 40153 AN XY: 51518

Gnomad4 AFR exome AF: 0.681

Gnomad4 AMR exome AF: 0.650

Gnomad4 ASJ exome AF: 0.837

Gnomad4 EAS exome AF: 0.644

Gnomad4 SAS exome AF: 0.716

Gnomad4 FIN exome AF: 0.785

Gnomad4 NFE exome AF: 0.814

Gnomad4 OTH exome AF: 0.788

GnomAD4 genome AF: 0.755 AC: 114950 AN: 152162 Hom.: 43735 Cov.: 34 AF XY: 0.753 AC XY: 56042 AN XY: 74400

Gnomad4 AFR AF: 0.687

Gnomad4 AMR AF: 0.681

Gnomad4 ASJ AF: 0.860

Gnomad4 EAS AF: 0.627

Gnomad4 SAS AF: 0.715

Gnomad4 FIN AF: 0.797

Gnomad4 NFE AF: 0.814

Gnomad4 OTH AF: 0.764

Alfa AF: 0.800 Hom.: 82408

Bravo AF: 0.745

Asia WGS AF: 0.700 AC: 2436 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum, group G Benign:1

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

This variant is associated with the following publications: (PMID: 25644244, 22982416, 22981091, 22866149, 26338418) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	1.2
Dann	Benign	0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs751402; hg19: chr13-103498198;