rs1800069

Variant names:

• chr16-13947713-T-C
• rs1800069
• NM_005236.3:c.2117T>C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_005236.3(ERCC4):​c.2117T>C​(p.Ile706Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,614,150 control chromosomes in the GnomAD database, including 8 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 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (8 hom.)
• Consequence: ERCC4 NM_005236.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:7 O:1
• Conservation: PhyloP100: 7.45

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19945452).
• BP6: Variant 16-13947713-T-C is Benign according to our data. Variant chr16-13947713-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134142.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=5, not_provided=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00176 (268/152258) while in subpopulation AMR AF= 0.00327 (50/15292). AF 95% confidence interval is 0.00255. There are 0 homozygotes in gnomad4. There are 129 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC4	NM_005236.3	c.2117T>C	p.Ile706Thr	missense_variant	Exon 11 of 11	ENST00000311895.8	NP_005227.1
ERCC4	XM_011522424.4	c.2255T>C	p.Ile752Thr	missense_variant	Exon 12 of 12		XP_011520726.1
ERCC4	XM_047433774.1	c.1328T>C	p.Ile443Thr	missense_variant	Exon 8 of 8		XP_047289730.1
ERCC4	XM_011522427.2	c.767T>C	p.Ile256Thr	missense_variant	Exon 6 of 6		XP_011520729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC4	ENST00000311895.8	c.2117T>C	p.Ile706Thr	missense_variant	Exon 11 of 11	1	NM_005236.3	ENSP00000310520.7

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 268 AN: 152258 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00276

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00147 AC: 369 AN: 251444 Hom.: 1 AF XY: 0.00137 AC XY: 186 AN XY: 135896

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00254

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00250 AC: 3652 AN: 1461892 Hom.: 8 Cov.: 32 AF XY: 0.00234 AC XY: 1703 AN XY: 727248

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000487

Gnomad4 NFE exome AF: 0.00308

Gnomad4 OTH exome AF: 0.00190

GnomAD4 genome AF: 0.00176 AC: 268 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.00173 AC XY: 129 AN XY: 74388

Gnomad4 AFR AF: 0.000555

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00276

Gnomad4 OTH AF: 0.00239

Alfa AF: 0.00242 Hom.: 1

Bravo AF: 0.00178

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000683 AC: 3

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00140 AC: 170

EpiCase AF: 0.00240

EpiControl AF: 0.00326

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1 Other:1

Dec 05, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

May 26, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ERCC4 c.2117T>C (p.Ile706Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 251444 control chromosomes (gnomAD), predominantly at a frequency of 0.0025 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 13 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. Six ClinVar submitters have assessed the variant since 2014: five classified the variant as of uncertain significance and one as benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Uncertain:2

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ERCC4 p.Ile706Thr variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs1800069), LOVD 3.0 and ClinVar (classified as uncertain significance by Genetic Services Laboratory, University of Chicage, and as likely benign by Invitae). The variant was identified in control databases in 366 of 268308 chromosomes (1 homozygous) at a frequency of 0.001364 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 283 of 118142 chromosomes (freq: 0.002395), Other in 12 of 6702 chromosomes (freq: 0.001791), Latino in 50 of 35108 chromosomes (freq: 0.001424), European (Finnish) in 11 of 25108 chromosomes (freq: 0.000438), African in 9 of 23614 chromosomes (freq: 0.000381) and Ashkenazi Jewish in 1 of 9858 chromosomes (freq: 0.000101), but was not observed in the East Asian or South Asian populations. The p.Ile706 residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Fanconi anemia complementation group Q Uncertain:1 Benign:1

Mar 03, 2021

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Mar 14, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ERCC4 c.2117T>C (p.Ile706Thr) missense change has a maximum subpopulation frequency of 0.31% in gnomAD v4.0.0 with 8 homozygotes (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with ataxia (PMID: 31692161), head and neck squamous cell carcinoma (PMID: 28678401), and pancreatic ductal adenocarcinoma (PMID: 28767289). To our knowledge, this variant has not been reported in individuals with Fanconi anemia or Xeroderma pigmentosum. In summary, this variant meets criteria to be classified as likely benign. -

XFE progeroid syndrome Uncertain:1

May 09, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Xeroderma pigmentosum, group F Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

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

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Xeroderma pigmentosum Benign:1

Nov 29, 2020

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Inborn genetic diseases Benign:1

Oct 16, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ERCC4-related disorder Benign:1

Feb 10, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Hereditary cancer-predisposing syndrome Benign:1

Oct 17, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BA1 c.2117T>C, located in exon 11 of the ERCC4 gene, is predicted to result in the substitution of Isoleucine by Threonine at codon 706, p.(Ile706Thr). The variant allele was found in 283/118142 alleles (1 homozygote), with a filtering allele frequency of 0,22% at 95% confidence, within the NFE population in the gnomAD v2.1.1 database (non-cancer data set) (BA1). Additional information has not been evaluated for this variant. Based on the currently available information, c.2117T>C is classified as a benign variant according to ACMG guidelines. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.76
MPC		0.48
ClinPred		0.040	T
GERP RS		5.5
Varity_R		0.82
gMVP		0.69

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: rs1800069; hg19: chr16-14041570; COSMIC: COSV99043584;