rs1800124

Positions:

chr16-13948220-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005236.3(ERCC4):c.2624A>G(p.Glu875Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 1,614,176 control chromosomes in the GnomAD database, including 255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 16 hom., cov: 32)

Exomes 𝑓: 0.016 ( 239 hom. )

Consequence

ERCC4
NM_005236.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 8.70

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:

ERCC4 (HGNC:):

ERCC4 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=0.008160144).

BP6

Variant 16-13948220-A-G is Benign according to our data. Variant chr16-13948220-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 129008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-13948220-A-G is described in Lovd as [Likely_benign]. Variant chr16-13948220-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0119 (1817/152290) while in subpopulation NFE AF= 0.0167 (1136/68020). AF 95% confidence interval is 0.0159. There are 16 homozygotes in gnomad4. There are 919 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC4	NM_005236.3 linkuse as main transcript	c.2624A>G	p.Glu875Gly	missense_variant	11/11	ENST00000311895.8	NP_005227.1	Q92889-1A0A1W1GSK9
ERCC4	XM_011522424.4 linkuse as main transcript	c.2762A>G	p.Glu921Gly	missense_variant	12/12		XP_011520726.1	A0A804HKF9
ERCC4	XM_047433774.1 linkuse as main transcript	c.1835A>G	p.Glu612Gly	missense_variant	8/8		XP_047289730.1
ERCC4	XM_011522427.2 linkuse as main transcript	c.1274A>G	p.Glu425Gly	missense_variant	6/6		XP_011520729.1	B4DXD8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC4	ENST00000311895.8 linkuse as main transcript	c.2624A>G	p.Glu875Gly	missense_variant	11/11	1	NM_005236.3	ENSP00000310520.7		Q92889-1

Frequencies

GnomAD3 genomes

AF:

0.0119

AC:

1815

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00333

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0117

Gnomad ASJ

AF:

0.0144

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.0215

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0167

Gnomad OTH

AF:

0.0201

GnomAD3 exomes

AF:

0.0133

AC:

3345

AN:

251420

Hom.:

AF XY:

0.0136

AC XY:

1845

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00332

Gnomad AMR exome

AF:

0.0101

Gnomad ASJ exome

AF:

0.0174

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00287

Gnomad FIN exome

AF:

0.0208

Gnomad NFE exome

AF:

0.0187

Gnomad OTH exome

AF:

0.0160

GnomAD4 exome

AF:

0.0157

AC:

22892

AN:

1461886

Hom.:

239

Cov.:

AF XY:

0.0156

AC XY:

11315

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00272

Gnomad4 AMR exome

AF:

0.0106

Gnomad4 ASJ exome

AF:

0.0175

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00303

Gnomad4 FIN exome

AF:

0.0206

Gnomad4 NFE exome

AF:

0.0176

Gnomad4 OTH exome

AF:

0.0147

GnomAD4 genome

AF:

0.0119

AC:

1817

AN:

152290

Hom.:

Cov.:

AF XY:

0.0123

AC XY:

919

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00334

Gnomad4 AMR

AF:

0.0117

Gnomad4 ASJ

AF:

0.0144

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.0215

Gnomad4 NFE

AF:

0.0167

Gnomad4 OTH

AF:

0.0199

Alfa

AF:

0.0177

Hom.:

Bravo

AF:

0.0118

TwinsUK

AF:

0.0159

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.00432

AC:

ESP6500EA

AF:

0.0174

AC:

150

ExAC

AF:

0.0131

AC:

1591

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2019	This variant is associated with the following publications: (PMID: 28051113, 17419091, 24728327, 20061190, 22374244, 15886521, 10479728, 24465539, 18767034, 28690523, 19626602, 24704021, 24004570) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 17, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3Other: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, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Xeroderma pigmentosum, group F

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

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

- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Vantari Genetics

Dec 11, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0082

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

PrimateAI

Benign

0.37

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.29

Sift

Uncertain

0.010

Sift4G

Uncertain

0.020

Polyphen

0.94

Vest4

0.18

MPC

0.28

ClinPred

0.026

GERP RS

6.2

Varity_R

0.55

gMVP

0.37

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