rs2020958

Positions:

chr16-13937838-A-G

Variant summary

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

The NM_005236.3(ERCC4):c.1884A>G(p.Glu628=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,612,194 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 44 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 43 hom. )

Consequence

ERCC4
NM_005236.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.990

Variant links:

Genes affected

ERCC4 (HGNC:3436): (ERCC excision repair 4, endonuclease catalytic subunit) The protein encoded by this gene forms a complex with ERCC1 and is involved in the 5' incision made during nucleotide excision repair. This complex is a structure specific DNA repair endonuclease that interacts with EME1. Defects in this gene are a cause of xeroderma pigmentosum complementation group F (XP-F), or xeroderma pigmentosum VI (XP6).[provided by RefSeq, Mar 2009]

ERCC4 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=-0.44).

BP6

Variant 16-13937838-A-G is Benign according to our data. Variant chr16-13937838-A-G is described in ClinVar as [Benign]. Clinvar id is 317817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-13937838-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.99 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.013 (1980/152304) while in subpopulation AFR AF= 0.0445 (1851/41566). AF 95% confidence interval is 0.0428. There are 44 homozygotes in gnomad4. There are 936 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	HGVSp	Effect	#exon/exons	MANE	Protein
ERCC4	NM_005236.3 linkuse as main transcript	c.1884A>G	p.Glu628=	synonymous_variant	9/11	ENST00000311895.8	NP_005227.1
ERCC4	XM_011522424.4 linkuse as main transcript	c.2022A>G	p.Glu674=	synonymous_variant	10/12		XP_011520726.1
ERCC4	XM_047433774.1 linkuse as main transcript	c.1095A>G	p.Glu365=	synonymous_variant	6/8		XP_047289730.1
ERCC4	XM_011522427.2 linkuse as main transcript	c.534A>G	p.Glu178=	synonymous_variant	4/6		XP_011520729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC4	ENST00000311895.8 linkuse as main transcript	c.1884A>G	p.Glu628=	synonymous_variant	9/11	1	NM_005236.3	ENSP00000310520	P1	Q92889-1

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1974

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0445

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00681

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00909

GnomAD3 exomes

AF:

0.00338

AC:

849

AN:

251268

Hom.:

AF XY:

0.00230

AC XY:

313

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.0466

Gnomad AMR exome

AF:

0.00200

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00132

AC:

1933

AN:

1459890

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

817

AN XY:

726404

show subpopulations

Gnomad4 AFR exome

AF:

0.0459

Gnomad4 AMR exome

AF:

0.00237

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000874

Gnomad4 OTH exome

AF:

0.00310

GnomAD4 genome

AF:

0.0130

AC:

1980

AN:

152304

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

936

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0445

Gnomad4 AMR

AF:

0.00680

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00947

Alfa

AF:

0.00364

Hom.:

Bravo

AF:

0.0146

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Xeroderma pigmentosum, group F

Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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. -

Cockayne syndrome;C0268140:Xeroderma pigmentosum, group F;C3808988:Fanconi anemia complementation group Q

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

- -

ERCC4-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

7.7

DANN

Benign

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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