Variant 5-60918267-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PM2PP3PP5_Moderate

The NM_000082.4(ERCC8):c.397C>T(p.Gln133Ter) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.000000694 in 1,441,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ERCC8
NM_000082.4 stop_gained, splice_region

Scores

Splicing: ADA: 0.9966

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.92

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 Pathogenic. Variant got 13 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

PP5

Variant 5-60918267-G-A is Pathogenic according to our data. Variant chr5-60918267-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 984262.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC8	NM_000082.4 linkuse as main transcript	c.397C>T	p.Gln133Ter	stop_gained, splice_region_variant	4/12	ENST00000676185.1	NP_000073.1
ERCC8-AS1	NR_183288.1 linkuse as main transcript	n.380-28G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC8	ENST00000676185.1 linkuse as main transcript	c.397C>T	p.Gln133Ter	stop_gained, splice_region_variant	4/12		NM_000082.4	ENSP00000501614	P1	Q13216-1
ERCC8-AS1	ENST00000457499.1 linkuse as main transcript	n.79-28G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1441480

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718400

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.14e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cockayne syndrome type 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Mar 11, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.91

MutationTaster

Benign

1.0

A;A;N

Vest4

0.86

ClinPred

1.0

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.91

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.24

Position offset: -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