rs3117

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 26 publications found

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]

ERCC8 Gene-Disease associations (from GenCC):

• Cockayne syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, PanelApp Australia, ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P
• UV-sensitive syndrome 2

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• Cockayne syndrome type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• UV-sensitive syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• 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	ENST00000676185.1	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

African (AFR) AF: 0.372 AC: 6690 AN: 17982

American (AMR) AF: 0.272 AC: 6602 AN: 24252

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 8274 AN: 19474

East Asian (EAS) AF: 0.0528 AC: 1819 AN: 34442

South Asian (SAS) AF: 0.331 AC: 20125 AN: 60732

European-Finnish (FIN) AF: 0.379 AC: 18695 AN: 49368

Middle Eastern (MID) AF: 0.437 AC: 1837 AN: 4206

European-Non Finnish (NFE) AF: 0.387 AC: 199586 AN: 516200

Other (OTH) AF: 0.366 AC: 13383 AN: 36536

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

African (AFR) AF: 0.373 AC: 15437 AN: 41404

American (AMR) AF: 0.316 AC: 4831 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.428 AC: 1484 AN: 3464

East Asian (EAS) AF: 0.0564 AC: 292 AN: 5178

South Asian (SAS) AF: 0.328 AC: 1579 AN: 4808

European-Finnish (FIN) AF: 0.360 AC: 3795 AN: 10540

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.394 AC: 26779 AN: 67962

Other (OTH) AF: 0.377 AC: 796 AN: 2110

Alfa AF: 0.384 Hom.: 15637

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		-0.66
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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