Variant chr5-60874157-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.30

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 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_multiple_submitters_no_conflicts, 2 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 GnomAd4 at 44 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC8	ENST00000676185.1 linkuse as main transcript	c.*458T>C		3_prime_UTR_variant	12/12		NM_000082.4	P1	Q13216-1

Frequencies

GnomAD3 genomes

AF:

0.0176

AC:

2671

AN:

152192

Hom.:

Cov.:

show subpopulations

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:

AN:

1158

Hom.:

Cov.:

AF XY:

0.0272

AC XY:

AN XY:

588

show subpopulations

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.:

Cov.:

AF XY:

0.0177

AC XY:

1319

AN XY:

74470

show subpopulations

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.:

Bravo

AF:

0.0161

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over