dbSNP rs2298881: ERCC1:c.-8+123G>T (chr19-45423658-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001983.4(ERCC1):c.-8+123G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,274,624 control chromosomes in the GnomAD database, including 11,398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1572 hom., cov: 31)

Exomes 𝑓: 0.12 ( 9826 hom. )

Consequence

ERCC1
NM_001983.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.115

Variant links:

Genes affected

ERCC1 (HGNC:3433): (ERCC excision repair 1, endonuclease non-catalytic subunit) The product of this gene functions in the nucleotide excision repair pathway, and is required for the repair of DNA lesions such as those induced by UV light or formed by electrophilic compounds including cisplatin. The encoded protein forms a heterodimer with the XPF endonuclease (also known as ERCC4), and the heterodimeric endonuclease catalyzes the 5' incision in the process of excising the DNA lesion. The heterodimeric endonuclease is also involved in recombinational DNA repair and in the repair of inter-strand crosslinks. Mutations in this gene result in cerebrooculofacioskeletal syndrome, and polymorphisms that alter expression of this gene may play a role in carcinogenesis. Multiple transcript variants encoding different isoforms have been found for this gene. The last exon of this gene overlaps with the CD3e molecule, epsilon associated protein gene on the opposite strand. [provided by RefSeq, Oct 2009]

ERCC1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 19-45423658-C-A is Benign according to our data. Variant chr19-45423658-C-A is described in ClinVar as [Benign]. Clinvar id is 1227955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC1	NM_001983.4 link	c.-8+123G>T		intron_variant	Intron 1 of 9	ENST00000300853.8	NP_001974.1	P07992-1A0A024R0Q6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC1	ENST00000300853.8 link	c.-8+123G>T		intron_variant	Intron 1 of 9	1	NM_001983.4	ENSP00000300853.3		P07992-1

Frequencies

GnomAD3 genomes

AF:

0.131

AC:

19868

AN:

151594

Hom.:

1571

Cov.:

show subpopulations

Gnomad AFR

AF:

0.129

Gnomad AMI

AF:

0.0989

Gnomad AMR

AF:

0.0996

Gnomad ASJ

AF:

0.121

Gnomad EAS

AF:

0.400

Gnomad SAS

AF:

0.255

Gnomad FIN

AF:

0.165

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.106

Gnomad OTH

AF:

0.129

GnomAD4 exome

AF:

0.117

AC:

131619

AN:

1122910

Hom.:

9826

Cov.:

AF XY:

0.119

AC XY:

64025

AN XY:

535870

show subpopulations

Gnomad4 AFR exome

AF:

0.131

Gnomad4 AMR exome

AF:

0.0927

Gnomad4 ASJ exome

AF:

0.129

Gnomad4 EAS exome

AF:

0.421

Gnomad4 SAS exome

AF:

0.241

Gnomad4 FIN exome

AF:

0.154

Gnomad4 NFE exome

AF:

0.101

Gnomad4 OTH exome

AF:

0.131

GnomAD4 genome

AF:

0.131

AC:

19869

AN:

151714

Hom.:

1572

Cov.:

AF XY:

0.136

AC XY:

10097

AN XY:

74106

show subpopulations

Gnomad4 AFR

AF:

0.129

Gnomad4 AMR

AF:

0.0996

Gnomad4 ASJ

AF:

0.121

Gnomad4 EAS

AF:

0.399

Gnomad4 SAS

AF:

0.255

Gnomad4 FIN

AF:

0.165

Gnomad4 NFE

AF:

0.106

Gnomad4 OTH

AF:

0.128

Alfa

AF:

0.104

Hom.:

569

Bravo

AF:

0.123

Asia WGS

AF:

0.300

AC:

1043

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26056042, 18451256, 23166636, 22374244) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

5.6

DANN

Benign

0.52

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