3-14158882-G-T

Variant names:

• chr3-14158882-G-T
• rs74737358
• NM_004628.5:c.1001C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004628.5(XPC):​c.1001C>A​(p.Pro334His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,613,868 control chromosomes in the GnomAD database, including 34 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. P334S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0075 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (15 hom.)
• Consequence: XPC NM_004628.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:9 O:1
• Conservation: PhyloP100: 1.30
• Publications: 25 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=0.0046908855).
• BP6: Variant 3-14158882-G-T is Benign according to our data. Variant chr3-14158882-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00749 (1140/152194) while in subpopulation AFR AF = 0.0237 (983/41508). AF 95% confidence interval is 0.0225. There are 19 homozygotes in GnomAd4. There are 541 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPC	NM_004628.5	c.1001C>A	p.Pro334His	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.1001C>A	p.Pro334His	missense_variant	Exon 9 of 16	1	NM_004628.5	ENSP00000285021.8

Frequencies

GnomAD3 genomes AF: 0.00748 AC: 1137 AN: 152076 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0237

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00258 AC: 637 AN: 247062 AF XY: 0.00200

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.00835

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.00364

GnomAD4 exome AF: 0.00106 AC: 1554 AN: 1461674 Hom.: 15 Cov.: 32 AF XY: 0.000937 AC XY: 681 AN XY: 727120

African (AFR) AF: 0.0253 AC: 846 AN: 33480

American (AMR) AF: 0.00335 AC: 150 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00758 AC: 198 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00261 AC: 15 AN: 5746

European-Non Finnish (NFE) AF: 0.000186 AC: 207 AN: 1111868

Other (OTH) AF: 0.00225 AC: 136 AN: 60368

GnomAD4 genome AF: 0.00749 AC: 1140 AN: 152194 Hom.: 19 Cov.: 32 AF XY: 0.00727 AC XY: 541 AN XY: 74408

African (AFR) AF: 0.0237 AC: 983 AN: 41508

American (AMR) AF: 0.00418 AC: 64 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00835 AC: 29 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68008

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00308 Hom.: 6

Bravo AF: 0.00861

ESP6500AA AF: 0.0268 AC: 84

ESP6500EA AF: 0.000977 AC: 7

ExAC AF: 0.00286 AC: 345

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000771

ClinVar

Significance: Benign/Likely benign

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

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum, group C Pathogenic:1 Uncertain:1 Benign:3

Dec 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

NM_004628.4:c.1001C>A (p.Pro334His) was previously reported as P218H. This variant has an allele frequency of 0.026 in African subpopulation in the gnomAD database. It has been reported previously in individuals with Xeroderma Pigmentosum in homozygous state (PMID: 17079196, 17084680). Functional studies show p.Pro334His mutation prevents the stimulation of Ogg1 glycosylase because it thwarts the interaction between XPC and Ogg1 (PMID: 18809580). Benign computational verdict because benign predictions from DEOGEN2, EIGEN, FATHMM-MKL, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT vs 1 pathogenic prediction from DANN and the position is not conserved. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: BS1, BP4, BP1, PS3, PM3_Supporting. -

not provided Benign:3

Sep 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

XPC: BP4, BS1, BS2 -

Dec 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 18955168, 8298653, 25333069, 17079196, 29973595, 30516811, 30675318, 31816862, 24728327, 18809580, 30256826, 27153395) -

not specified Benign:1 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Feb 18, 2022

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.1001C>A (p.Pro334His) 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 0.0026 in 247062 control chromosomes, predominantly at a frequency of 0.025 within the African or African-American subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 35 fold of the estimated maximal expected allele frequency for a pathogenic variant in XPC causing Xeroderma Pigmentosum phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1001C>A has been reported in the literature (example, Bonache_2018, Li_1993, Martin-Morales_2018, Maxwell_2016, Pugh_2019, Ramirez-Calvo_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Xeroderma Pigmentosum. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (example, BernardesdeJesus_2008, Bidon_2018). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Xeroderma pigmentosum Benign:1

Mar 26, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

XPC-related disorder Benign:1

Apr 10, 2021

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	0.099
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.3
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.078
Sift	Benign	0.10	T
Sift4G	Benign	0.10	T
Polyphen		0.85	P
Vest4		0.68
MVP		0.17
MPC		0.29
ClinPred		0.0062	T
GERP RS		3.1
Varity_R		0.085
gMVP		0.24
Mutation Taster		=87/13	polymorphism

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: rs74737358; hg19: chr3-14200382; COSMIC: COSV99034868;