rs3117

Variant names:

• chr5-60874510-A-G
• rs3117
• NM_000082.4:c.*105T>C

Variant summary

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

The NM_000082.4(ERCC8):​c.*105T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 915,126 control chromosomes in the GnomAD database, including 63,483 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10479 hom., cov: 31)
  • Exomes 𝑓: 0.36 (53004 hom.)
• Consequence: ERCC8 NM_000082.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.661

Genes affected

ERCC8 (HGNC:3439): (ERCC excision repair 8, CSA ubiquitin ligase complex subunit) This gene encodes a WD repeat protein, which interacts with Cockayne syndrome type B (CSB) protein and with p44 protein, a subunit of the RNA polymerase II transcription factor IIH. Mutations in this gene have been identified in patients with hereditary disease Cockayne syndrome (CS). CS cells are abnormally sensitive to ultraviolet radiation and are defective in the repair of transcriptionally active genes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-60874510-A-G is Benign according to our data. Variant chr5-60874510-A-G is described in ClinVar as [Benign]. Clinvar id is 354011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC8	NM_000082.4	c.*105T>C		3_prime_UTR_variant	Exon 12 of 12	ENST00000676185.1	NP_000073.1
ERCC8	NM_001007233.3	c.*105T>C		3_prime_UTR_variant	Exon 13 of 13		NP_001007234.1
ERCC8	NM_001290285.2	c.*105T>C		3_prime_UTR_variant	Exon 11 of 11		NP_001277214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC8	ENST00000676185	c.*105T>C		3_prime_UTR_variant	Exon 12 of 12		NM_000082.4	ENSP00000501614.1

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55224 AN: 151816 Hom.: 10463 Cov.: 31

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.428

Gnomad EAS AF: 0.0563

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.381

GnomAD4 exome AF: 0.363 AC: 277011 AN: 763192 Hom.: 53004 Cov.: 10 AF XY: 0.364 AC XY: 144467 AN XY: 397414

Gnomad4 AFR exome AF: 0.372

Gnomad4 AMR exome AF: 0.272

Gnomad4 ASJ exome AF: 0.425

Gnomad4 EAS exome AF: 0.0528

Gnomad4 SAS exome AF: 0.331

Gnomad4 FIN exome AF: 0.379

Gnomad4 NFE exome AF: 0.387

Gnomad4 OTH exome AF: 0.366

GnomAD4 genome AF: 0.364 AC: 55271 AN: 151934 Hom.: 10479 Cov.: 31 AF XY: 0.360 AC XY: 26757 AN XY: 74270

Gnomad4 AFR AF: 0.373

Gnomad4 AMR AF: 0.316

Gnomad4 ASJ AF: 0.428

Gnomad4 EAS AF: 0.0564

Gnomad4 SAS AF: 0.328

Gnomad4 FIN AF: 0.360

Gnomad4 NFE AF: 0.394

Gnomad4 OTH AF: 0.377

Alfa AF: 0.385 Hom.: 11180

Bravo AF: 0.359

Asia WGS AF: 0.182 AC: 632 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 09, 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

- -

Cockayne syndrome type 1 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.6
DANN	Benign	0.75

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: rs3117; hg19: chr5-60170337; COSMIC: COSV54015045;