rs1799802

Positions:

chr16-13934224-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3BP4_StrongBS2

The NM_005236.3(ERCC4):c.1135C>T(p.Pro379Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,611,848 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0045 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0057 ( 32 hom. )

Consequence

ERCC4
NM_005236.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8O:1

Conservation

PhyloP100: 7.57

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 -7 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.011538804).

BS2

High Homozygotes in GnomAdExome4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC4	NM_005236.3 linkuse as main transcript	c.1135C>T	p.Pro379Ser	missense_variant	7/11	ENST00000311895.8	NP_005227.1	Q92889-1A0A1W1GSK9
ERCC4	XM_011522424.4 linkuse as main transcript	c.1273C>T	p.Pro425Ser	missense_variant	8/12		XP_011520726.1	A0A804HKF9
ERCC4	XM_047433774.1 linkuse as main transcript	c.346C>T	p.Pro116Ser	missense_variant	4/8		XP_047289730.1
ERCC4	XM_011522427.2 linkuse as main transcript	c.-216C>T		5_prime_UTR_variant	2/6		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.1135C>T	p.Pro379Ser	missense_variant	7/11	1	NM_005236.3	ENSP00000310520.7		Q92889-1

Frequencies

GnomAD3 genomes

AF:

0.00451

AC:

680

AN:

150838

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000951

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00431

Gnomad ASJ

AF:

0.000578

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00971

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00683

Gnomad OTH

AF:

0.00242

GnomAD3 exomes

AF:

0.00400

AC:

1003

AN:

250774

Hom.:

AF XY:

0.00416

AC XY:

564

AN XY:

135640

show subpopulations

Gnomad AFR exome

AF:

0.000991

Gnomad AMR exome

AF:

0.00185

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00101

Gnomad FIN exome

AF:

0.00721

Gnomad NFE exome

AF:

0.00607

Gnomad OTH exome

AF:

0.00507

GnomAD4 exome

AF:

0.00567

AC:

8286

AN:

1460892

Hom.:

Cov.:

AF XY:

0.00548

AC XY:

3981

AN XY:

726776

show subpopulations

Gnomad4 AFR exome

AF:

0.000956

Gnomad4 AMR exome

AF:

0.00197

Gnomad4 ASJ exome

AF:

0.00153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000997

Gnomad4 FIN exome

AF:

0.00787

Gnomad4 NFE exome

AF:

0.00655

Gnomad4 OTH exome

AF:

0.00558

GnomAD4 genome

AF:

0.00450

AC:

680

AN:

150956

Hom.:

Cov.:

AF XY:

0.00470

AC XY:

346

AN XY:

73614

show subpopulations

Gnomad4 AFR

AF:

0.000948

Gnomad4 AMR

AF:

0.00430

Gnomad4 ASJ

AF:

0.000578

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00971

Gnomad4 NFE

AF:

0.00683

Gnomad4 OTH

AF:

0.00239

Alfa

AF:

0.00517

Hom.:

Bravo

AF:

0.00375

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00581

AC:

ExAC

AF:

0.00373

AC:

453

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00507

EpiControl

AF:

0.00587

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ENSG00000262732: BS2; ERCC4: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 06, 2015	- -

not specified

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 24, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 08, 2022	Variant summary: ERCC4 c.1135C>T (p.Pro379Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.004 in 250774 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately 20 fold of the estimated maximal expected allele frequency for a pathogenic variant in ERCC4 causing Xeroderma Pigmentosum phenotype (0.00019), strongly suggesting that the variant is benign. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=2), likely benign (n=1) and VUS (n=2). Based on the evidence outlined above, the variant was classified as benign. -

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 28, 2024

- -

Xeroderma pigmentosum

Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Nov 11, 2020

- -

ERCC4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2019

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

Xeroderma pigmentosum, group F

Benign:1

Likely 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Xeroderma pigmentosum, group F;C1970416:XFE progeroid syndrome;C3808988:Fanconi anemia complementation group Q

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Aug 23, 2022

This variant has been reported in the literature in the compound heterozygous and homozygous states in at least 3 individuals with mild xeroderma pigmentosum (Ahmad 2010 PMID:20221251; Fassihi 2016 PMID:26884178). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.7% [463/67788], including in 7 total homozygotes; https://gnomad.broadinstitute.org/variant/16-13934224-C-T?dataset=gnomad_r3), and is present in ClinVar (Variation ID:134148). Evolutionary conservation and computational predictive tools for this variant are unclear. Functional studies have shown a mildly deleterious effect of this variant on some aspects of protein function, while minimal to no effect on other aspects (Ahmad 2010 PMID:20221251; Sabatella 2018 PMID:30165384). However, these studies may not accurately represent in vivo biological function. This variant may confer a slight increase in the risk for sunburn (OR: 1.31, 95% CI [1.257, 1.431]) (Backman 2021 PMID:34662886). In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.012

MetaSVM

Uncertain

0.24

MutationAssessor

Pathogenic

3.9

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-7.9

REVEL

Uncertain

0.53

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.71

MVP

0.91

MPC

0.45

ClinPred

0.13

GERP RS

5.9

Varity_R

0.72

gMVP

0.79

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