rs121965090

Variant names:

• chr3-14158706-G-A
• rs121965090
• NM_004628.5:c.1177C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-14158706-G-A
• chr3-14158706-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_004628.5(XPC):​c.1177C>T​(p.Arg393Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,613,848 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict 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. R393Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: XPC NM_004628.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1 O:1
• Conservation: PhyloP100: 0.165

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007992059).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000927 (141/152138) while in subpopulation NFE AF = 0.00165 (112/68016). AF 95% confidence interval is 0.0014. There are 0 homozygotes in GnomAd4. There are 59 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPC	NM_004628.5	c.1177C>T	p.Arg393Trp	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.1177C>T	p.Arg393Trp	missense_variant	Exon 9 of 16	1	NM_004628.5	ENSP00000285021.8

Frequencies

GnomAD3 genomes AF: 0.000928 AC: 141 AN: 152020 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000883 AC: 220 AN: 249252 AF XY: 0.000850

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.00165

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.00136 AC: 1984 AN: 1461710 Hom.: 2 Cov.: 32 AF XY: 0.00130 AC XY: 946 AN XY: 727136

Gnomad4 AFR exome AF: 0.000269 AC: 9 AN: 33480

Gnomad4 AMR exome AF: 0.000693 AC: 31 AN: 44724

Gnomad4 ASJ exome AF: 0.0000765 AC: 2 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.0000348 AC: 3 AN: 86258

Gnomad4 FIN exome AF: 0.0000562 AC: 3 AN: 53400

Gnomad4 NFE exome AF: 0.00169 AC: 1880 AN: 1111870

Gnomad4 Remaining exome AF: 0.000894 AC: 54 AN: 60374

GnomAD4 genome AF: 0.000927 AC: 141 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.000793 AC XY: 59 AN XY: 74368

Gnomad4 AFR AF: 0.000385 AC: 0.000385394 AN: 0.000385394

Gnomad4 AMR AF: 0.000719 AC: 0.000719048 AN: 0.000719048

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00165 AC: 0.00164667 AN: 0.00164667

Gnomad4 OTH AF: 0.000473 AC: 0.000473485 AN: 0.000473485

Alfa AF: 0.00137 Hom.: 0

Bravo AF: 0.000846

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00126 AC: 9

ExAC AF: 0.000793 AC: 96

EpiCase AF: 0.00115

EpiControl AF: 0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

XPC: BP4 -

Apr 03, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies support a damaging effect: moderate reduction in recruitment of XPC protein to focal DNA damage (Qiao et al., 2011); Observed in individuals with colorectal, bladder, and other cancers, as well as in healthy controls (Qiao et al., 2011; Bodian et al., 2014; Matejcic et al., 2021); This variant is associated with the following publications: (PMID: 21273643, 35530314, 24728327, 33627384) -

Dec 21, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 393 of the XPC protein (p.Arg393Trp). This variant is present in population databases (rs121965090, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with XPC-related conditions. ClinVar contains an entry for this variant (Variation ID: 135484). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt XPC protein function with a negative predictive value of 80%. 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. -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Xeroderma pigmentosum, group C Uncertain:3

Feb 09, 2021

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Mar 10, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

May 23, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: XPC c.1177C>T (p.Arg393Trp) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00088 in 249252 control chromosomes. The observed variant frequency is higher than the estimated maximal expected allele frequency for a pathogenic variant in XPC causing Xeroderma Pigmentosum phenotype (0.00071). To our knowledge, no occurrence of c.1177C>T in individuals affected with Xeroderma Pigmentosum has been reported. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. The authors report a moderate reduction in recruitment of XPC protein to focal DNA damage in an in-vitro system utilizing GFP-tagged XPC plasmids (Qiao_2011). The following publication have been ascertained in the context of this evaluation (PMID: 21273643). ClinVar contains an entry for this variant (Variation ID: 135484). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Xeroderma pigmentosum Uncertain:1

Nov 25, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.90
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.031
Sift	Benign	0.087	T
Sift4G	Benign	0.10	T
Polyphen		0.0010	B
Vest4		0.12
MVP		0.11
MPC		0.12
ClinPred		0.029	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.21
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

Publications

LitVar

Other links and lift over

dbSNP: rs121965090; hg19: chr3-14200206; COSMIC: COSV104373862;