rs121965090

Positions:

• chr3-14158706-G-A

Variant summary

Our verdict is Benign. Variant got -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). 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: Uncertain significance criteria provided, multiple submitters, no conflicts U:10 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

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. 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/exons	MANE	UniProt
XPC	NM_004628.5	c.1177C>T	p.Arg393Trp	missense_variant	9/16	ENST00000285021.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XPC	ENST00000285021.12	c.1177C>T	p.Arg393Trp	missense_variant	9/16	1	NM_004628.5	P1
XPC-AS1	ENST00000627116.2	n.457-7170G>A		intron_variant, non_coding_transcript_variant		5

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

GnomAD3 exomes AF: 0.000883 AC: 220 AN: 249252 Hom.: 0 AF XY: 0.000850 AC XY: 115 AN XY: 135220

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 SAS exome AF: 0.0000980

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

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00169

Gnomad4 OTH exome AF: 0.000894

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

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00165

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00140 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: Uncertain significance

Submissions summary: Uncertain:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 21, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 17, 2022	This sequence change replaces arginine with tryptophan at codon 393 of the XPC protein (p.Arg393Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt XPC protein function. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2023	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) -

Xeroderma pigmentosum, group C Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 09, 2021	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 10, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

not specified Uncertain:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2022	Variant summary: XPC c.1177C>T (p.Arg393Trp) 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 0.00088 in 249252 control chromosomes. The observed variant frequency is approximately 1.25 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 benign. To our knowledge, no penetrant association 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). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Xeroderma pigmentosum Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Nov 25, 2021

- -

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
MutationTaster	Benign	1.0	N;N
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

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; COSMIC: COSV104373862;