3-14145949-G-T

Position:

chr3-14145949-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.83

Variant links:

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 links:

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

XPC-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
XPC	NM_004628.5 linkuse as main transcript	c.2815C>A	p.Gln939Lys	missense_variant	16/16	ENST00000285021.12	NP_004619.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPC	ENST00000285021.12 linkuse as main transcript	c.2815C>A	p.Gln939Lys	missense_variant	16/16	1	NM_004628.5	ENSP00000285021	P1	Q01831-1

Frequencies

GnomAD3 genomes

AF:

0.648

AC:

98325

AN:

151840

Hom.:

32144

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.607

AC XY:

437096

AN XY:

719594

show subpopulations

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.:

AF XY:

0.653

AC XY:

48518

AN XY:

74250

show subpopulations

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:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	XPC: BP4, BS1, BS2 -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Claritas Genomics	Jun 20, 2012	- -
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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.041

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.50

MetaRNN

Benign

0.0000013

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-2.5

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.37

PROVEAN

Benign

1.7

REVEL

Benign

0.095

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.023

MPC

0.15

ClinPred

0.0028

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over