rs1800069

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_005236.3(ERCC4):ā€‹c.2117T>Cā€‹(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: š‘“ 0.0018 ( 0 hom., cov: 32)
Exomes š‘“: 0.0025 ( 8 hom. )

Consequence

ERCC4
NM_005236.3 missense

Scores

6
7
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:6O:1

Conservation

PhyloP100: 7.45
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 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, Uncertain_significance=5, not_provided=1, Benign=2}.
BS2
High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ERCC4NM_005236.3 linkuse as main transcriptc.2117T>C p.Ile706Thr missense_variant 11/11 ENST00000311895.8 NP_005227.1 Q92889-1A0A1W1GSK9
ERCC4XM_011522424.4 linkuse as main transcriptc.2255T>C p.Ile752Thr missense_variant 12/12 XP_011520726.1 A0A804HKF9
ERCC4XM_047433774.1 linkuse as main transcriptc.1328T>C p.Ile443Thr missense_variant 8/8 XP_047289730.1
ERCC4XM_011522427.2 linkuse as main transcriptc.767T>C p.Ile256Thr missense_variant 6/6 XP_011520729.1 B4DXD8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ERCC4ENST00000311895.8 linkuse as main transcriptc.2117T>C p.Ile706Thr missense_variant 11/111 NM_005236.3 ENSP00000310520.7 Q92889-1

Frequencies

GnomAD3 genomes
AF:
0.00176
AC:
268
AN:
152258
Hom.:
0
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:6Benign:6Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:1Other:1
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 26, 2022Variant 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. -
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoDec 05, 2016- -
not provided, no classification providedreference populationITMISep 19, 2013- -
not provided Uncertain:2
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-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. -
Uncertain significance, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Fanconi anemia complementation group Q Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalMar 14, 2024The 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. -
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMar 03, 2021This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
XFE progeroid syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMay 09, 2019This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Xeroderma pigmentosum, group F Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Xeroderma pigmentosum Benign:1
Likely benign, criteria provided, single submittercurationSema4, Sema4Nov 29, 2020- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsOct 16, 2021This 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
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 10, 2022This 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). -

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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