3-14158408-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004628.5(XPC):c.1475G>A(p.Arg492His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0504 in 1,613,866 control chromosomes in the GnomAD database, including 2,337 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.040 ( 167 hom., cov: 32)

Exomes 𝑓: 0.052 ( 2170 hom. )

Consequence

XPC
NM_004628.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: -0.190

Variant links:

Genes affected

XPC (HGNC:12816): (XPC complex subunit, DNA damage recognition and repair factor) The protein encoded by this gene is a key component of the XPC complex, which plays an important role in the early steps of global genome nucleotide excision repair (NER). The encoded protein is important for damage sensing and DNA binding, and shows a preference for single-stranded DNA. Mutations in this gene or some other NER components can result in Xeroderma pigmentosum, a rare autosomal recessive disorder characterized by increased sensitivity to sunlight with the development of carcinomas at an early age. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2017]

XPC links:

XPC-AS1 (HGNC:55014): (XPC antisense RNA 1)

XPC-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001995474).

BP6

Variant 3-14158408-C-T is Benign according to our data. Variant chr3-14158408-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 135489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPC	NM_004628.5 link	c.1475G>A	p.Arg492His	missense_variant	Exon 9 of 16	ENST00000285021.12	NP_004619.3	Q01831-1X5DRB1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPC	ENST00000285021.12 link	c.1475G>A	p.Arg492His	missense_variant	Exon 9 of 16	1	NM_004628.5	ENSP00000285021.8		Q01831-1

Frequencies

GnomAD3 genomes

AF:

0.0397

AC:

6037

AN:

152088

Hom.:

167

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0109

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0459

Gnomad ASJ

AF:

0.0763

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.0358

Gnomad FIN

AF:

0.0295

Gnomad MID

AF:

0.0318

Gnomad NFE

AF:

0.0584

Gnomad OTH

AF:

0.0612

GnomAD3 exomes

AF:

0.0421

AC:

10493

AN:

249056

Hom.:

305

AF XY:

0.0435

AC XY:

5880

AN XY:

135130

show subpopulations

Gnomad AFR exome

AF:

0.0100

Gnomad AMR exome

AF:

0.0313

Gnomad ASJ exome

AF:

0.0687

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.0406

Gnomad FIN exome

AF:

0.0272

Gnomad NFE exome

AF:

0.0572

Gnomad OTH exome

AF:

0.0473

GnomAD4 exome

AF:

0.0515

AC:

75295

AN:

1461660

Hom.:

2170

Cov.:

AF XY:

0.0513

AC XY:

37310

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.00887

Gnomad4 AMR exome

AF:

0.0327

Gnomad4 ASJ exome

AF:

0.0679

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0402

Gnomad4 FIN exome

AF:

0.0284

Gnomad4 NFE exome

AF:

0.0572

Gnomad4 OTH exome

AF:

0.0468

GnomAD4 genome

AF:

0.0397

AC:

6036

AN:

152206

Hom.:

167

Cov.:

AF XY:

0.0395

AC XY:

2938

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0109

Gnomad4 AMR

AF:

0.0459

Gnomad4 ASJ

AF:

0.0763

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.0354

Gnomad4 FIN

AF:

0.0295

Gnomad4 NFE

AF:

0.0584

Gnomad4 OTH

AF:

0.0601

Alfa

AF:

0.0549

Hom.:

454

Bravo

AF:

0.0384

TwinsUK

AF:

0.0491

AC:

182

ALSPAC

AF:

0.0560

AC:

216

ESP6500AA

AF:

0.0128

AC:

ESP6500EA

AF:

0.0613

AC:

439

ExAC

AF:

0.0423

AC:

5109

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0566

EpiControl

AF:

0.0567

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27153395, 17119055, 24728327) -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Xeroderma pigmentosum, group C

Benign:3

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Aug 27, 2018

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: XPC c.1475G>A (p.Arg492His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.042 in 276928 control chromosomes in the gnomAD database, including 338 homozygotes. The observed variant frequency is approximately 29-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in XPC causing Xeroderma Pigmentosum phenotype (0.0014), strongly suggesting that the variant is benign. c.1475G>A has been reported in the literature in individuals affected with Xeroderma Pigmentosum (Tamhankar_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Xeroderma Pigmentosum . Co-occurrences with other pathogenic variant(s) in a homozygous state has been reported (XPC c.1243C>T, p.R415X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as "likely benign." Based on the evidence outlined above, the variant was classified as benign. -

Xeroderma pigmentosum group A

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

XPC-related disorder

Benign:1

Jul 23, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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

Benign

0.074

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.60

CADD

Benign

1.5

DANN

Benign

0.90

DEOGEN2

Benign

0.11

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.27

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PrimateAI

Benign

0.20

PROVEAN

Benign

-1.1

REVEL

Benign

0.012

Sift

Benign

0.23

Sift4G

Benign

0.11

Polyphen

0.0

Vest4

0.011

MPC

0.15

ClinPred

0.0042

GERP RS

-4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.014

gMVP

0.12

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