rs145201970

Positions:

chr2-127288840-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000122.2(ERCC3):c.847C>T(p.Arg283Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,613,538 control chromosomes in the GnomAD database, including 1 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 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 1 hom. )

Consequence

ERCC3
NM_000122.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:1O:1

Conservation

PhyloP100: 9.92

Variant links:

Genes affected

ERCC3 (HGNC:3435): (ERCC excision repair 3, TFIIH core complex helicase subunit) This gene encodes an ATP-dependent DNA helicase that functions in nucleotide excision repair. The encoded protein is a subunit of basal transcription factor 2 (TFIIH) and, therefore, also functions in class II transcription. Mutations in this gene are associated with Xeroderma pigmentosum B, Cockayne's syndrome, and trichothiodystrophy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ERCC3 links:

ERCC3 (HGNC:):

ERCC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19793788).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC3	NM_000122.2 linkuse as main transcript	c.847C>T	p.Arg283Cys	missense_variant	7/15	ENST00000285398.7	NP_000113.1	P19447

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC3	ENST00000285398.7 linkuse as main transcript	c.847C>T	p.Arg283Cys	missense_variant	7/15	1	NM_000122.2	ENSP00000285398.2		P19447

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

214

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000755

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00182

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000847

AC:

213

AN:

251462

Hom.:

AF XY:

0.000861

AC XY:

117

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000554

Gnomad NFE exome

AF:

0.00137

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.00160

AC:

2344

AN:

1461288

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

1164

AN XY:

727002

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000730

Gnomad4 NFE exome

AF:

0.00196

Gnomad4 OTH exome

AF:

0.00108

GnomAD4 genome

AF:

0.00141

AC:

214

AN:

152250

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000755

Gnomad4 NFE

AF:

0.00182

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00138

Hom.:

Bravo

AF:

0.00135

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000873

AC:

106

EpiCase

AF:

0.000872

EpiControl

AF:

0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 283 of the ERCC3 protein (p.Arg283Cys). This variant is present in population databases (rs145201970, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with melanoma and prostate cancer (PMID: 28259476, 30414346). ClinVar contains an entry for this variant (Variation ID: 134128). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ERCC3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal and family history of melanoma or breast cancer (Bonache 2018, Potjer 2019); This variant is associated with the following publications: (PMID: 24728327, 30306255, 30414346) -

not specified

Uncertain:2Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 14, 2023	Variant summary: ERCC3 c.847C>T (p.Arg283Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00085 in 251462 control chromosomes (gnomAD). The observed variant frequency is approximately 8-fold of the estimated maximal expected allele frequency for a pathogenic variant in ERCC3 causing Xeroderma Pigmentosum phenotype (0.00011), strongly suggesting that the variant could be benign. c.847C>T has been reported in the literature in individuals as not co-segregating with the melanoma phenotype in two affected members from at least one family (Potjer_2019). It has additionally been reported in individuals affected with breast cancer (Bonache_2018, VanMarke_2020) and prostate cancer (Mateo_2020) as well as an individual from a cohort of healthy controls (n=681) (Bodian_2014). Since the penetrance of Xeroderma Pigmentosum due to this variant appears to be lower than expected, no conclusions can be drawn from these data. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24728327, 30306255, 31874108, 31664448, 30414346, 32295625). Eight ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 13, 2015	- -

Xeroderma pigmentosum

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Oct 28, 2021

- -

Xeroderma pigmentosum group B;C4225344:Trichothiodystrophy 2, photosensitive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Xeroderma pigmentosum group B

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Trichothiodystrophy 2, photosensitive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 24, 2019

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

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.54

D;.

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.077

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Pathogenic

3.3

M;.

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-7.6

D;.

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.0040

D;.

Polyphen

0.77

P;.

Vest4

0.90

MVP

0.76

MPC

1.1

ClinPred

0.20

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.89

gMVP

0.83

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