rs374117852

Positions:

chr3-14152376-T-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_004628.5(XPC):c.2074A>T(p.Lys692Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

XPC
NM_004628.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.72

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-14152376-T-A is Pathogenic according to our data. Variant chr3-14152376-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 496267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XPC	NM_004628.5 linkuse as main transcript	c.2074A>T	p.Lys692Ter	stop_gained	11/16	ENST00000285021.12
XPC-AS1	XR_001740603.2 linkuse as main transcript	n.2576T>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XPC	ENST00000285021.12 linkuse as main transcript	c.2074A>T	p.Lys692Ter	stop_gained	11/16	1	NM_004628.5	P1	Q01831-1
XPC-AS1	ENST00000627116.2 linkuse as main transcript	n.456+2379T>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461104

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726742

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Xeroderma pigmentosum, group C

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Apr 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -

Xeroderma pigmentosum

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 06, 2017

Variant summary: The XPC c.2074A>T (p.Lys692*) variant results in a premature termination codon, predicted to cause a truncated or absent XPC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. These predictions were confirmed by Khan et al (2006) who showed severely reduced level of mRNA and lack of protein expression in in vitro assay. This variant was found in 1/108904 control chromosomes at a frequency of 0.0000092, which does not exceed the estimated maximal expected allele frequency of a pathogenic XPC variant (0.0014142). This variant has been reported in at least two unrelated patients with Xeroderma Pigmentosum (Khan_2006, Kuschal_2013). In addition, truncation variants downstream of this position, such as c.2152C>T (p.R718*), c.2262delC (p.Asn754Lysfs) and c.2251-1G>C have been classified as "Pathogenic" by reputable databases/diagnostic laboratories . Taken together, this variant is classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 20, 2023

This sequence change creates a premature translational stop signal (p.Lys692*) in the XPC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in XPC are known to be pathogenic (PMID: 23173980, 25256075). This variant is present in population databases (rs374117852, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with xeroderma pigmentosum (PMID: 16081512). ClinVar contains an entry for this variant (Variation ID: 496267). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.80

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

A;A

Vest4

0.98

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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