5-60918301-A-G

Position:

chr5-60918301-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000082.4(ERCC8):c.363T>C(p.Asp121=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,598,376 control chromosomes in the GnomAD database, including 324 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 19 hom., cov: 32)

Exomes 𝑓: 0.019 ( 305 hom. )

Consequence

ERCC8
NM_000082.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.38

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:

ERCC8-AS1 (HGNC:40220): (ERCC8 antisense RNA 1)

ERCC8-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.26).

BP6

Variant 5-60918301-A-G is Benign according to our data. Variant chr5-60918301-A-G is described in ClinVar as [Benign]. Clinvar id is 190176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-60918301-A-G is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=3.38 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0131 (1998/152216) while in subpopulation NFE AF= 0.0215 (1460/67970). AF 95% confidence interval is 0.0206. There are 19 homozygotes in gnomad4. There are 912 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC8	NM_000082.4 linkuse as main transcript	c.363T>C	p.Asp121=	synonymous_variant	4/12	ENST00000676185.1	NP_000073.1
ERCC8-AS1	NR_183288.1 linkuse as main transcript	n.386A>G		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC8	ENST00000676185.1 linkuse as main transcript	c.363T>C	p.Asp121=	synonymous_variant	4/12		NM_000082.4	ENSP00000501614	P1	Q13216-1
ERCC8-AS1	ENST00000457499.1 linkuse as main transcript	n.85A>G		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.0131

AC:

1999

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00350

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0135

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0182

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0215

Gnomad OTH

AF:

0.0191

GnomAD3 exomes

AF:

0.0150

AC:

3751

AN:

250230

Hom.:

AF XY:

0.0159

AC XY:

2150

AN XY:

135252

show subpopulations

Gnomad AFR exome

AF:

0.00283

Gnomad AMR exome

AF:

0.0102

Gnomad ASJ exome

AF:

0.0121

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0220

Gnomad FIN exome

AF:

0.00372

Gnomad NFE exome

AF:

0.0208

Gnomad OTH exome

AF:

0.0212

GnomAD4 exome

AF:

0.0191

AC:

27650

AN:

1446160

Hom.:

305

Cov.:

AF XY:

0.0194

AC XY:

13963

AN XY:

720530

show subpopulations

Gnomad4 AFR exome

AF:

0.00365

Gnomad4 AMR exome

AF:

0.0104

Gnomad4 ASJ exome

AF:

0.0112

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0193

Gnomad4 FIN exome

AF:

0.00439

Gnomad4 NFE exome

AF:

0.0215

Gnomad4 OTH exome

AF:

0.0187

GnomAD4 genome

AF:

0.0131

AC:

1998

AN:

152216

Hom.:

Cov.:

AF XY:

0.0123

AC XY:

912

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00349

Gnomad4 AMR

AF:

0.0135

Gnomad4 ASJ

AF:

0.00692

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0178

Gnomad4 FIN

AF:

0.00292

Gnomad4 NFE

AF:

0.0215

Gnomad4 OTH

AF:

0.0194

Alfa

AF:

0.0180

Hom.:

Bravo

AF:

0.0136

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.0224

EpiControl

AF:

0.0226

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Claritas Genomics	Nov 16, 2012	- -

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

-0.26

CADD

Benign

DANN

Benign

0.85

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