3-14158408-C-T

Variant names:

• chr3-14158408-C-T
• rs2227999
• NM_004628.5:c.1475G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R492C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.040 (167 hom., cov: 32)
  • Exomes 𝑓: 0.052 (2170 hom.)
• Consequence: XPC NM_004628.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.190
• Publications: 32 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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	c.1475G>A	p.Arg492His	missense_variant	Exon 9 of 16	ENST00000285021.12	NP_004619.3

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0397 AC: 6037 AN: 152088 Hom.: 167 Cov.: 32

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

GnomAD2 exomes AF: 0.0421 AC: 10493 AN: 249056 AF XY: 0.0435

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 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.: 33 AF XY: 0.0513 AC XY: 37310 AN XY: 727110

African (AFR) AF: 0.00887 AC: 297 AN: 33480

American (AMR) AF: 0.0327 AC: 1463 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0679 AC: 1775 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0402 AC: 3466 AN: 86258

European-Finnish (FIN) AF: 0.0284 AC: 1518 AN: 53384

Middle Eastern (MID) AF: 0.0517 AC: 298 AN: 5768

European-Non Finnish (NFE) AF: 0.0572 AC: 63647 AN: 1111844

Other (OTH) AF: 0.0468 AC: 2827 AN: 60374

GnomAD4 genome AF: 0.0397 AC: 6036 AN: 152206 Hom.: 167 Cov.: 32 AF XY: 0.0395 AC XY: 2938 AN XY: 74424

African (AFR) AF: 0.0109 AC: 453 AN: 41532

American (AMR) AF: 0.0459 AC: 702 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0763 AC: 265 AN: 3472

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5156

South Asian (SAS) AF: 0.0354 AC: 171 AN: 4826

European-Finnish (FIN) AF: 0.0295 AC: 313 AN: 10608

Middle Eastern (MID) AF: 0.0342 AC: 10 AN: 292

European-Non Finnish (NFE) AF: 0.0584 AC: 3974 AN: 67998

Other (OTH) AF: 0.0601 AC: 127 AN: 2112

Alfa AF: 0.0517 Hom.: 617

Bravo AF: 0.0384

TwinsUK AF: 0.0491 AC: 182

ALSPAC AF: 0.0560 AC: 216

ESP6500AA AF: 0.0128 AC: 40

ESP6500EA AF: 0.0613 AC: 439

ExAC AF: 0.0423 AC: 5109

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.0566

EpiControl AF: 0.0567

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum, group C Benign:3

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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) -

not specified Benign:1 Other:1

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. -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

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	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	1.5
DANN	Benign	0.90
DEOGEN2	Benign	0.11	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.19
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.012
Sift	Benign	0.23	T
Sift4G	Benign	0.11	T
Polyphen		0.0	B
Vest4		0.011
MPC		0.15
ClinPred		0.0042	T
GERP RS		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.014
gMVP		0.12
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2227999; hg19: chr3-14199908; COSMIC: COSV53203815; COSMIC: COSV53203815;