rs121913016

Positions:

chr19-45357368-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP3BS2

The NM_000400.4(ERCC2):c.1381C>G(p.Leu461Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000857 in 1,613,648 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L461P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00090 ( 9 hom. )

Consequence

ERCC2
NM_000400.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5B:4O:1

Conservation

PhyloP100: 8.35

Variant links:

Genes affected

ERCC2 (HGNC:3434): (ERCC excision repair 2, TFIIH core complex helicase subunit) The nucleotide excision repair pathway is a mechanism to repair damage to DNA. The protein encoded by this gene is involved in transcription-coupled nucleotide excision repair and is an integral member of the basal transcription factor BTF2/TFIIH complex. The gene product has ATP-dependent DNA helicase activity and belongs to the RAD3/XPD subfamily of helicases. Defects in this gene can result in three different disorders, the cancer-prone syndrome xeroderma pigmentosum complementation group D, trichothiodystrophy, and Cockayne syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

ERCC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a region_of_interest Mediates interaction with MMS19 (size 199) in uniprot entity ERCC2_HUMAN there are 29 pathogenic changes around while only 7 benign (81%) in NM_000400.4

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC2	NM_000400.4 linkuse as main transcript	c.1381C>G	p.Leu461Val	missense_variant	15/23	ENST00000391945.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC2	ENST00000391945.10 linkuse as main transcript	c.1381C>G	p.Leu461Val	missense_variant	15/23	1	NM_000400.4	P1	P18074-1

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00704

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000411

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00120

AC:

302

AN:

251138

Hom.:

AF XY:

0.00153

AC XY:

207

AN XY:

135730

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00239

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00712

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000379

Gnomad OTH exome

AF:

0.000979

GnomAD4 exome

AF:

0.000895

AC:

1308

AN:

1461292

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

809

AN XY:

726946

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00222

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00696

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000510

Gnomad4 OTH exome

AF:

0.000944

GnomAD4 genome

AF:

0.000492

AC:

AN:

152356

Hom.:

Cov.:

AF XY:

0.000523

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00705

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000411

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000625

Hom.:

Bravo

AF:

0.000287

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00133

AC:

162

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:5Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Xeroderma pigmentosum, group D

Pathogenic:2Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	May 13, 2019	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2,PP3,PP5. -
Pathogenic, flagged submission	literature only	OMIM	Jan 01, 1997	- -
Likely pathogenic, flagged submission	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 14, 2022	- -
Uncertain significance, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000400.3:c.1381C>G in the ERCC2 gene has an allele frequency of 0.007 in South Asian subpopulation in the gnomAD database. The functional study (GM436 cells) demenstrated Leu461Val exits in apparent absence of expression of the other XPD allele. Hence, the Leu461Val allele can be assumed not to interfere with the essential function of the XPD (ERCC2) gene product (PMID: 7849702). Takayama et al reported a patient with typical trichothiodystrophy characteristics, harboring Leu461Val and a deletion of amino acids 716-730 in one allele and Ala725Pro in the other allele; the pathogenicity of Ala725Pro, however, is not determined (PMID: 9195225). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ERCC2: PP3, BS1:Supporting, BS3:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2023	Published functional studies of the A717G;L461V complex allele demonstrated a reduced TFIIH binding capacity with partial NER activity compared to wild-type, but no functional data for Leu461Val on its own exist (Horibata et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 15982307, 18470933, 23221806, 10064601, 24728327, 22234153, 8571952, 12116233, 10447254, 23232694, 19681155, 9238033, 26884178, 7849702, 7585650, 9195225, 12393803, 16135823, 12820975, 27504877, 29607586, 30136158, 34426522, 31980526, 26556299, 25716912, 31589614, 33726816, 36253817, 37179334) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified

Benign:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 04, 2023	Variant summary: ERCC2 c.1381C>G (p.Leu461Val) results in a 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 0.0012 in 251138 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in ERCC2 causing Xeroderma Pigmentosum phenotype (0.00061), strongly suggesting that the variant is benign. c.1381C>G has been reported in the literature always a complex allele in cis with c.2150C>G (p.Ala717Gly) in compound heterozygous genotypes with other pathogenic alleles in multiple individuals with features of Xeroderma Pigmentosum and Trichothiodystrophy (example, Takayama_1996, Moslehi_2012, Fujimoto_2005, Zhou_2013, Fassihi_2016, Horibata_2015). This complex allele has also been reported in individuals with various cancers, although these findings have not been ascertained in the context of this evaluation. These report(s) do not provide unequivocal conclusions about association of the variant in isolation with Xeroderma Pigmentosum/Trichothiodystrophy. At least one publication reports experimental evidence evaluating an impact on protein function (Horibata_2015). These results showed no damaging effect of this variant in isolation, as it possessed full Nucleotide Excision Repair (NER) activity (comparable to p.WT). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant in isolation was classified as likely benign. -

Trichothiodystrophy 1, photosensitive

Pathogenic:1

Pathogenic, flagged submission

literature only

OMIM

Jan 01, 1997

- -

Xeroderma pigmentosum

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Oct 11, 2021

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2022

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

Pathogenic

0.66

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;T;T

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Uncertain

0.44

MutationAssessor

Pathogenic

3.4

M;.;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.4

N;N;.

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0020

D;D;.

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

0.98

D;D;.

Vest4

0.96

MVP

0.87

MPC

0.62

ClinPred

0.16

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.51

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.75

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.75

Position offset: -1

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