5-60874378-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000082.4(ERCC8):c.*237T>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 0.0115 in 495,818 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (13 hom., cov: 32)
  • Exomes 𝑓: 0.011 (40 hom.)
• Consequence: ERCC8 NM_000082.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0830

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=-0.86).
• BP6: Variant 5-60874378-A-G is Benign according to our data. Variant chr5-60874378-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 354010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.012 (1830/152312) while in subpopulation SAS AF= 0.0269 (130/4826). AF 95% confidence interval is 0.0232. There are 13 homozygotes in gnomad4. There are 894 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC8	NM_000082.4	c.*237T>C		3_prime_UTR_variant	12/12	ENST00000676185.1
ERCC8	NM_001007233.3	c.*237T>C		3_prime_UTR_variant	13/13
ERCC8	NM_001290285.2	c.*237T>C		3_prime_UTR_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC8	ENST00000676185.1	c.*237T>C		3_prime_UTR_variant	12/12		NM_000082.4	P1

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1834 AN: 152194 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.0271

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.00813

GnomAD4 exome AF: 0.0113 AC: 3892 AN: 343506 Hom.: 40 Cov.: 3 AF XY: 0.0124 AC XY: 2273 AN XY: 182954

Gnomad4 AFR exome AF: 0.0197

Gnomad4 AMR exome AF: 0.00456

Gnomad4 ASJ exome AF: 0.0246

Gnomad4 EAS exome AF: 0.000966

Gnomad4 SAS exome AF: 0.0272

Gnomad4 FIN exome AF: 0.00427

Gnomad4 NFE exome AF: 0.0100

Gnomad4 OTH exome AF: 0.00977

GnomAD4 genome AF: 0.0120 AC: 1830 AN: 152312 Hom.: 13 Cov.: 32 AF XY: 0.0120 AC XY: 894 AN XY: 74482

Gnomad4 AFR AF: 0.0188

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.0269

Gnomad4 FIN AF: 0.00433

Gnomad4 NFE AF: 0.0102

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.0112 Hom.: 5

Bravo AF: 0.0117

Asia WGS AF: 0.0140 AC: 50 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 2018

- -

Cockayne syndrome type 1 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.54
Dann	Benign	0.42

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: rs4647153; hg19: chr5-60170205;