rs754532049

Positions:

chr3-14158238-GCA-G

Variant summary

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

The NM_004628.5(XPC):c.1643_1644del(p.Val548AlafsTer25) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000105 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.0000082 ( 0 hom. )

Consequence

XPC
NM_004628.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 4.57

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 3-14158238-GCA-G is Pathogenic according to our data. Variant chr3-14158238-GCA-G is described in ClinVar as [Pathogenic]. Clinvar id is 262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14158238-GCA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XPC	NM_004628.5 linkuse as main transcript	c.1643_1644del	p.Val548AlafsTer25	frameshift_variant	9/16	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.1643_1644del	p.Val548AlafsTer25	frameshift_variant	9/16	1	NM_004628.5	ENSP00000285021	P1	Q01831-1
XPC-AS1	ENST00000627116.2 linkuse as main transcript	n.457-7633_457-7632del		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

249358

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135252

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461710

Hom.:

AF XY:

0.0000110

AC XY:

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152098

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Xeroderma pigmentosum, group C

Pathogenic:7Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 10, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2009	- -
Pathogenic, criteria provided, single submitter	research	Medical Molecular Genetics Department, National Research Center	Dec 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000000262, PMID:8298653). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000020, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Claritas Genomics	Mar 18, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 16, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 22, 2020	The XPC c.1643_1644delTG p.(Val548AlafsTer25) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant is reported in the literature to be a founder variant in the North African population and has been reported in a homozygous state in at least 84 individuals with a phenotype consistent with xeroderma pigmentosum (Soufir et al. 2010; Sehnaji et al. 2013; Bensenouci et al. 2016). The highest frequency of this allele in the Genome Aggregation database is 0.000116 in the Admixed American population (version 2.1.1). Based on the available evidence the c.1643_1644delTG p.(Val548AlafsTer25) variant is classified as pathogenic for xeroderma pigmentosum. -

not provided

Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	XPC: PS4, PVS1:Strong, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change creates a premature translational stop signal (p.Val548Alafs*25) 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 (rs754532049, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with xeroderma pigmentosum (PMID: 20054342, 23143338, 27413738). It is commonly reported in individuals of North African ancestry (PMID: 20054342, 23143338, 27413738). ClinVar contains an entry for this variant (Variation ID: 262). For these reasons, this variant has been classified as Pathogenic. -

Xeroderma pigmentosum

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 19, 2017

Variant summary: The XPC c.1643_1644delTG (p.Val548AlafsX25) 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. One in silico tool predicts a damaging outcome for this variant. Functional studies showed absence of XPC protein expression in lymphoblasts from XP patients and reduced post-UV unscheduled DNA synthesis (Khan_2006). This variant was found in 5/246258 control chromosomes at a frequency of 0.0000203, which does not exceed the estimated maximal expected allele frequency of a pathogenic XPC variant (0.0014142). This variant is considered a founder mutation and is reported in 87% of XP-C cases from North Africa (Bensenouci_2016, El-Harith_2012, Khan_2006). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Feb 25, 2020

ACMG classification criteria: PVS1, PS4, PM2 -

XPC-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2023

The XPC c.1643_1644delTG variant is predicted to result in a frameshift and premature protein termination (p.Val548Alafs*25). This variant has been frequently reported in the homozygous or compound heterozygous state in individuals with xeroderma pigmentosum group C and it is considered a founder variant in North African populations (see for example, Mahindra et al. 2008. PubMed ID: 19119101; Ben Rakaya et al. 2009. PubMed ID: 19478817; Soufir et al. 2010. PubMed ID: 20054342; Santiago et al. 2020. PubMed ID: 32239545; Rabie et al. 2021. PubMed ID: 33672602). In vitro functional studies also support its pathogenicity (Schäfer et al. 2013. PubMed ID: 23173980). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in XPC are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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