13-102846195-C-T

Variant summary

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

The NM_000123.4(ERCC5):c.-72C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0448 in 1,310,150 control chromosomes in the GnomAD database, including 1,834 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (555 hom., cov: 32)
  • Exomes 𝑓: 0.041 (1279 hom.)
• Consequence: ERCC5 NM_000123.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.40

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 13-102846195-C-T is Benign according to our data. Variant chr13-102846195-C-T is described in ClinVar as [Benign]. Clinvar id is 310910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC5	NM_000123.4	c.-72C>T		5_prime_UTR_variant	1/15	ENST00000652225.2
BIVM-ERCC5	NM_001204425.2	c.1451-5923C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC5	ENST00000652225.2	c.-72C>T		5_prime_UTR_variant	1/15		NM_000123.4	P1

Frequencies

GnomAD3 genomes AF: 0.0711 AC: 10817 AN: 152046 Hom.: 551 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0363

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.0527

Gnomad SAS AF: 0.0516

Gnomad FIN AF: 0.0720

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0422

Gnomad OTH AF: 0.0728

GnomAD4 exome AF: 0.0413 AC: 47815 AN: 1157986 Hom.: 1279 Cov.: 16 AF XY: 0.0414 AC XY: 24114 AN XY: 582296

Gnomad4 AFR exome AF: 0.139

Gnomad4 AMR exome AF: 0.0280

Gnomad4 ASJ exome AF: 0.0404

Gnomad4 EAS exome AF: 0.0589

Gnomad4 SAS exome AF: 0.0480

Gnomad4 FIN exome AF: 0.0707

Gnomad4 NFE exome AF: 0.0353

Gnomad4 OTH exome AF: 0.0469

GnomAD4 genome AF: 0.0713 AC: 10847 AN: 152164 Hom.: 555 Cov.: 32 AF XY: 0.0707 AC XY: 5262 AN XY: 74406

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.0362

Gnomad4 ASJ AF: 0.0343

Gnomad4 EAS AF: 0.0529

Gnomad4 SAS AF: 0.0520

Gnomad4 FIN AF: 0.0720

Gnomad4 NFE AF: 0.0422

Gnomad4 OTH AF: 0.0716

Alfa AF: 0.0571 Hom.: 122

Bravo AF: 0.0706

Asia WGS AF: 0.0690 AC: 238 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 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	5.6
Dann	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

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: rs2296148; hg19: chr13-103498545; COSMIC: COSV57279527; COSMIC: COSV57279527;