rs4647100

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000082.4(ERCC8):c.435T>C(p.Tyr145=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 1,587,156 control chromosomes in the GnomAD database, including 50,035 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3499 hom., cov: 27)

Exomes 𝑓: 0.25 ( 46536 hom. )

Consequence

ERCC8
NM_000082.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.62

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 -16 ACMG points.

BP6

Variant 5-60904838-A-G is Benign according to our data. Variant chr5-60904838-A-G is described in ClinVar as [Benign]. Clinvar id is 190177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-60904838-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ERCC8	NM_000082.4 linkuse as main transcript	c.435T>C	p.Tyr145=	synonymous_variant	5/12	ENST00000676185.1
ERCC8	NM_001007233.3 linkuse as main transcript	c.261T>C	p.Tyr87=	synonymous_variant	6/13
ERCC8	NM_001007234.3 linkuse as main transcript	c.435T>C	p.Tyr145=	synonymous_variant	5/6
ERCC8	NM_001290285.2 linkuse as main transcript	c.23-1122T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC8	ENST00000676185.1 linkuse as main transcript	c.435T>C	p.Tyr145=	synonymous_variant	5/12		NM_000082.4	P1	Q13216-1

Frequencies

GnomAD3 genomes

AF:

0.195

AC:

29414

AN:

150696

Hom.:

3498

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0909

Gnomad AMI

AF:

0.113

Gnomad AMR

AF:

0.180

Gnomad ASJ

AF:

0.237

Gnomad EAS

AF:

0.00330

Gnomad SAS

AF:

0.192

Gnomad FIN

AF:

0.267

Gnomad MID

AF:

0.201

Gnomad NFE

AF:

0.265

Gnomad OTH

AF:

0.206

GnomAD3 exomes

AF:

0.205

AC:

51442

AN:

251058

Hom.:

6279

AF XY:

0.211

AC XY:

28649

AN XY:

135686

show subpopulations

Gnomad AFR exome

AF:

0.0854

Gnomad AMR exome

AF:

0.130

Gnomad ASJ exome

AF:

0.230

Gnomad EAS exome

AF:

0.00109

Gnomad SAS exome

AF:

0.192

Gnomad FIN exome

AF:

0.285

Gnomad NFE exome

AF:

0.262

Gnomad OTH exome

AF:

0.228

GnomAD4 exome

AF:

0.246

AC:

352696

AN:

1436350

Hom.:

46536

Cov.:

AF XY:

0.246

AC XY:

175846

AN XY:

715992

show subpopulations

Gnomad4 AFR exome

AF:

0.0806

Gnomad4 AMR exome

AF:

0.137

Gnomad4 ASJ exome

AF:

0.240

Gnomad4 EAS exome

AF:

0.000557

Gnomad4 SAS exome

AF:

0.195

Gnomad4 FIN exome

AF:

0.280

Gnomad4 NFE exome

AF:

0.267

Gnomad4 OTH exome

AF:

0.229

GnomAD4 genome

AF:

0.195

AC:

29417

AN:

150806

Hom.:

3499

Cov.:

AF XY:

0.194

AC XY:

14308

AN XY:

73676

show subpopulations

Gnomad4 AFR

AF:

0.0908

Gnomad4 AMR

AF:

0.180

Gnomad4 ASJ

AF:

0.237

Gnomad4 EAS

AF:

0.00331

Gnomad4 SAS

AF:

0.193

Gnomad4 FIN

AF:

0.267

Gnomad4 NFE

AF:

0.265

Gnomad4 OTH

AF:

0.203

Alfa

AF:

0.235

Hom.:

2231

Bravo

AF:

0.184

Asia WGS

AF:

0.0790

AC:

276

AN:

3454

EpiCase

AF:

0.267

EpiControl

AF:

0.257

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 17, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Claritas Genomics	Apr 30, 2012	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Cockayne syndrome type 1

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

UV-sensitive syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.22

Position offset: -46

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