5-60874157-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000082.4(ERCC8):c.*458T>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 0.0176 in 153,468 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (44 hom., cov: 32)
  • Exomes 𝑓: 0.022 (1 hom.)
• Consequence: ERCC8 NM_000082.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.30

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 5-60874157-A-G is Benign according to our data. Variant chr5-60874157-A-G is described in ClinVar as [Benign]. Clinvar id is 906686.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0175 (2672/152310) while in subpopulation NFE AF= 0.0237 (1610/68036). AF 95% confidence interval is 0.0227. There are 44 homozygotes in gnomad4. There are 1319 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 44 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC8	NM_000082.4	c.*458T>C		3_prime_UTR_variant	12/12	ENST00000676185.1
ERCC8	NM_001007233.3	c.*458T>C		3_prime_UTR_variant	13/13
ERCC8	NM_001290285.2	c.*458T>C		3_prime_UTR_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC8	ENST00000676185.1	c.*458T>C		3_prime_UTR_variant	12/12		NM_000082.4	P1

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2671 AN: 152192 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.00376

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.0384

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0236

Gnomad OTH AF: 0.0163

GnomAD4 exome AF: 0.0216 AC: 25 AN: 1158 Hom.: 1 Cov.: 0 AF XY: 0.0272 AC XY: 16 AN XY: 588

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0500

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0667

Gnomad4 NFE exome AF: 0.0220

Gnomad4 OTH exome AF: 0.0690

GnomAD4 genome AF: 0.0175 AC: 2672 AN: 152310 Hom.: 44 Cov.: 32 AF XY: 0.0177 AC XY: 1319 AN XY: 74470

Gnomad4 AFR AF: 0.00375

Gnomad4 AMR AF: 0.0177

Gnomad4 ASJ AF: 0.0369

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00890

Gnomad4 FIN AF: 0.0384

Gnomad4 NFE AF: 0.0237

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0206 Hom.: 3

Bravo AF: 0.0161

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cockayne syndrome type 1 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	1.7
Dann	Benign	0.88

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: rs4647156; hg19: chr5-60169984;