rs1800067

Positions:

Variant summary

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

The NM_005236.3(ERCC4):c.1244G>A(p.Arg415Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.068 in 1,613,408 control chromosomes in the GnomAD database, including 4,457 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.053 ( 326 hom., cov: 32)

Exomes 𝑓: 0.069 ( 4131 hom. )

Consequence

ERCC4
NM_005236.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 9.60

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030626655).

BP6

Variant 16-13935176-G-A is Benign according to our data. Variant chr16-13935176-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-13935176-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0754 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ERCC4	NM_005236.3 linkuse as main transcript	c.1244G>A	p.Arg415Gln	missense_variant	8/11	ENST00000311895.8	NP_005227.1
ERCC4	XM_011522424.4 linkuse as main transcript	c.1382G>A	p.Arg461Gln	missense_variant	9/12		XP_011520726.1
ERCC4	XM_047433774.1 linkuse as main transcript	c.455G>A	p.Arg152Gln	missense_variant	5/8		XP_047289730.1
ERCC4	XM_011522427.2 linkuse as main transcript	c.-107G>A		5_prime_UTR_variant	3/6		XP_011520729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC4	ENST00000311895.8 linkuse as main transcript	c.1244G>A	p.Arg415Gln	missense_variant	8/11	1	NM_005236.3	ENSP00000310520	P1	Q92889-1
	ENST00000570663.1 linkuse as main transcript	n.219+241C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0533

AC:

8111

AN:

152174

Hom.:

326

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0151

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.0662

Gnomad ASJ

AF:

0.113

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0352

Gnomad FIN

AF:

0.0376

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.0772

Gnomad OTH

AF:

0.0823

GnomAD3 exomes

AF:

0.0561

AC:

14090

AN:

251016

Hom.:

568

AF XY:

0.0586

AC XY:

7958

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.0129

Gnomad AMR exome

AF:

0.0452

Gnomad ASJ exome

AF:

0.123

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0390

Gnomad FIN exome

AF:

0.0354

Gnomad NFE exome

AF:

0.0765

Gnomad OTH exome

AF:

0.0733

GnomAD4 exome

AF:

0.0695

AC:

101541

AN:

1461116

Hom.:

4131

Cov.:

AF XY:

0.0695

AC XY:

50529

AN XY:

726926

show subpopulations

Gnomad4 AFR exome

AF:

0.0138

Gnomad4 AMR exome

AF:

0.0484

Gnomad4 ASJ exome

AF:

0.117

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0400

Gnomad4 FIN exome

AF:

0.0382

Gnomad4 NFE exome

AF:

0.0770

Gnomad4 OTH exome

AF:

0.0664

GnomAD4 genome

AF:

0.0532

AC:

8108

AN:

152292

Hom.:

326

Cov.:

AF XY:

0.0518

AC XY:

3856

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0150

Gnomad4 AMR

AF:

0.0660

Gnomad4 ASJ

AF:

0.113

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.0356

Gnomad4 FIN

AF:

0.0376

Gnomad4 NFE

AF:

0.0772

Gnomad4 OTH

AF:

0.0810

Alfa

AF:

0.0764

Hom.:

1246

Bravo

AF:

0.0539

TwinsUK

AF:

0.0763

AC:

283

ALSPAC

AF:

0.0810

AC:

312

ESP6500AA

AF:

0.0123

AC:

ESP6500EA

AF:

0.0765

AC:

658

ExAC

AF:

0.0556

AC:

6747

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.0881

EpiControl

AF:

0.0863

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2019	This variant is associated with the following publications: (PMID: 24802942, 27153395, 24651674) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.0031

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.31

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.27

MPC

0.46

ClinPred

0.037

GERP RS

5.8

Varity_R

0.67

gMVP

0.59

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