rs1799802

Positions:

• chr16-13934224-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3 BP4_Strong BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8 O:1
• Conservation: PhyloP100: 7.57

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]

(HGNC:):

ACMG classification

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	UniProt
ERCC4	NM_005236.3	c.1135C>T	p.Pro379Ser	missense_variant	7/11	ENST00000311895.8
ERCC4	XM_011522424.4	c.1273C>T	p.Pro425Ser	missense_variant	8/12
ERCC4	XM_047433774.1	c.346C>T	p.Pro116Ser	missense_variant	4/8
ERCC4	XM_011522427.2	c.-216C>T		5_prime_UTR_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC4	ENST00000311895.8	c.1135C>T	p.Pro379Ser	missense_variant	7/11	1	NM_005236.3	P1
	ENST00000570663.1	n.219+1193G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00451 AC: 680 AN: 150838 Hom.: 1 Cov.: 33

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.: 6 AF XY: 0.00416 AC XY: 564 AN XY: 135640

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.: 32 Cov.: 29 AF XY: 0.00548 AC XY: 3981 AN XY: 726776

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.: 1 Cov.: 33 AF XY: 0.00470 AC XY: 346 AN XY: 73614

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.: 4

Bravo AF: 0.00375

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00581 AC: 50

ExAC AF: 0.00373 AC: 453

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00507

EpiControl AF: 0.00587

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 06, 2015	- -
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	Jul 01, 2024	ENSG00000262732: BS2; ERCC4: BS2 -

not specified Benign:2 Other:1

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. -
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	- -

Cockayne syndrome;C0268140:Xeroderma pigmentosum, group F;C3808988:Fanconi anemia complementation group Q Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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, criteria provided, single submitter

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	T
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	3.9	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.71
MVP		0.91
MPC		0.45
ClinPred		0.13	T
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

Other links and lift over

dbSNP: rs1799802; hg19: chr16-14028081; COSMIC: COSV100318624; COSMIC: COSV100318624;