3-14145949-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004628.5(XPC):c.2815C>A(p.Gln939Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 1,602,772 control chromosomes in the GnomAD database, including 302,541 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 0.65 (32194 hom., cov: 31)
  • Exomes 𝑓: 0.61 (270347 hom.)
• Consequence: XPC NM_004628.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.83

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3247075E-6).
• BP6: Variant 3-14145949-G-T is Benign according to our data. Variant chr3-14145949-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 190215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XPC	NM_004628.5	c.2815C>A	p.Gln939Lys	missense_variant	16/16	ENST00000285021.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XPC	ENST00000285021.12	c.2815C>A	p.Gln939Lys	missense_variant	16/16	1	NM_004628.5	P1

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98325 AN: 151840 Hom.: 32144 Cov.: 31

Gnomad AFR AF: 0.726

Gnomad AMI AF: 0.669

Gnomad AMR AF: 0.671

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.637

Gnomad SAS AF: 0.657

Gnomad FIN AF: 0.699

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.593

Gnomad OTH AF: 0.645

GnomAD3 exomes AF: 0.633 AC: 156744 AN: 247442 Hom.: 50140 AF XY: 0.627 AC XY: 84174 AN XY: 134272

Gnomad AFR exome AF: 0.730

Gnomad AMR exome AF: 0.706

Gnomad ASJ exome AF: 0.528

Gnomad EAS exome AF: 0.639

Gnomad SAS exome AF: 0.647

Gnomad FIN exome AF: 0.698

Gnomad NFE exome AF: 0.592

Gnomad OTH exome AF: 0.604

GnomAD4 exome AF: 0.609 AC: 883010 AN: 1450814 Hom.: 270347 Cov.: 56 AF XY: 0.607 AC XY: 437096 AN XY: 719594

Gnomad4 AFR exome AF: 0.729

Gnomad4 AMR exome AF: 0.703

Gnomad4 ASJ exome AF: 0.528

Gnomad4 EAS exome AF: 0.617

Gnomad4 SAS exome AF: 0.646

Gnomad4 FIN exome AF: 0.692

Gnomad4 NFE exome AF: 0.597

Gnomad4 OTH exome AF: 0.603

GnomAD4 genome AF: 0.648 AC: 98450 AN: 151958 Hom.: 32194 Cov.: 31 AF XY: 0.653 AC XY: 48518 AN XY: 74250

Gnomad4 AFR AF: 0.726

Gnomad4 AMR AF: 0.671

Gnomad4 ASJ AF: 0.533

Gnomad4 EAS AF: 0.637

Gnomad4 SAS AF: 0.658

Gnomad4 FIN AF: 0.699

Gnomad4 NFE AF: 0.593

Gnomad4 OTH AF: 0.648

Alfa AF: 0.595 Hom.: 55531

Bravo AF: 0.649

TwinsUK AF: 0.593 AC: 2200

ALSPAC AF: 0.604 AC: 2326

ESP6500AA AF: 0.730 AC: 2775

ESP6500EA AF: 0.601 AC: 4949

ExAC AF: 0.631 AC: 76275

Asia WGS AF: 0.681 AC: 2368 AN: 3478

EpiCase AF: 0.570

EpiControl AF: 0.573

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Claritas Genomics	Jun 20, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 27, 2018	Variant summary: XPC c.2815C>A (p.Gln939Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.64 in 275306 control chromosomes, suggesting that it is the major allele and therefore benign. The observed variant frequency is approximately 450-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. The variant has been found to have a slightly associated increased risk for cancer (He_2013) however the relevance of this finding to an inherited cause of Xeroderma Pigmentosum is not unlikely. A ClinVar submisson 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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	This variant is associated with the following publications: (PMID: 20056640, 23819639, 20658464, 23400628, 15700316, 19027756, 23269608, 20193233, 14729591, 27153395) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	XPC: BP4, BS1, BS2 -

Xeroderma pigmentosum, group C Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -

Xeroderma pigmentosum Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	14
Dann	Benign	0.90
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.5	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.095
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.023
MPC		0.15
ClinPred		0.0028	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.080

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: rs2228001; hg19: chr3-14187449; COSMIC: COSV53207797; COSMIC: COSV53207797;