3-14148732-C-G

Variant summary

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

The NM_004628.5(XPC):​c.2251-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

XPC
NM_004628.5 splice_acceptor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

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

Conservation

PhyloP100: 7.70
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-AS1 (HGNC:55014): (XPC antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6, offset of 44, new splice context is: gtgtacctcttcctgcccAGcat. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-14148732-C-G is Pathogenic according to our data. Variant chr3-14148732-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 190213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
XPCNM_004628.5 linkc.2251-1G>C splice_acceptor_variant, intron_variant Intron 12 of 15 ENST00000285021.12 NP_004619.3 Q01831-1X5DRB1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
XPCENST00000285021.12 linkc.2251-1G>C splice_acceptor_variant, intron_variant Intron 12 of 15 1 NM_004628.5 ENSP00000285021.8 Q01831-1

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152212
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000241
AC:
6
AN:
249174
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135180
show subpopulations
Gnomad AFR exome
AF:
0.000323
Gnomad AMR exome
AF:
0.0000290
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000684
AC:
10
AN:
1461668
Hom.:
0
Cov.:
30
AF XY:
0.00000550
AC XY:
4
AN XY:
727104
show subpopulations
Gnomad4 AFR exome
AF:
0.000209
Gnomad4 AMR exome
AF:
0.0000447
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152212
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.000169
Gnomad4 AMR
AF:
0.000131
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
Alfa
AF:
0.000142
Hom.:
0
Bravo
AF:
0.000155
ExAC
AF:
0.0000165
AC:
2
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Xeroderma pigmentosum, group C Pathogenic:9
Dec 01, 2015
Medical Molecular Genetics Department, National Research Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Mar 21, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 01, 2021
DNA Repair Laboratory, Institute of Biomedical Sciences - University of Sao Paulo
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Oct 17, 2007
Claritas Genomics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Dr.Nikuei Genetic Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 17, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Nov 19, 2021
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

NM_004628.4(XPC):c.2251-1G>C is a canonical splice variant classified as pathogenic in the context of xeroderma pigmentosum group C. c.2251-1G>C has been observed in cases with relevant disease (PMID: 21482201). Functional assessments of this variant are not available in the literature. c.2251-1G>C has been observed in population frequency databases (gnomAD: AFR 0.04%). In summary, NM_004628.4(XPC):c.2251-1G>C is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Oct 31, 2022
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PM2 moderated, PM3 strong, PP1 supporting -

Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:3
Jun 01, 2021
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 25, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31930276, 21482201, 29753700, 26884178, 29569758, 31589614, 33672602) -

Jan 08, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 12 of the XPC gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs754673606, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with xeroderma pigmentosum (PMID: 21482201). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 190213). Studies have shown that disruption of this splice site results in abnormal splicing, including skipping of exon 13, retention of intron 12, and/or a deletion of 44 nucleotides in exon 13 and introduces a premature termination codon (PMID: 21482201). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Xeroderma pigmentosum Pathogenic:2
Jul 11, 2017
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The XPC c.2251-1G>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict a significant impact on normal splicing. Functional studies proved the exon skipping and the absence of the XPC protein associated with impaired DNA synthesis in XP patients cultured fibroblasts (Cartault_DNA_Repair_2011, Fassihi_PNAS_2016). This variant was found in 2/120678 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic XPC variant (0.0014142). This variant is reported in multiple homozygous XP patients (Cartault_DNA_Repair_2011, Fassihi_PNAS_2016). In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Jul 01, 2023
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

XPC-related disorder Pathogenic:1
Dec 21, 2023
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The XPC c.2251-1G>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in the homozygous or compound heterozygous state in individuals with xeroderma pigmentosum (see for example, Santiago et al. 2020. PubMed ID: 32239545; Fassihi et al. 2016. PubMed ID: 26884178; reported as IVS 12-1G>C in Cartault et al. 2011. PubMed ID: 21482201). This variant is reported in 0.025% of alleles in individuals of African descent in gnomAD. Variants that disrupt the consensus splice acceptor site in XPC are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.25
CADD
Pathogenic
34
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
0.98
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.9

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.93
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.63
Position offset: -45
DS_AL_spliceai
0.93
Position offset: -1

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.

Other links and lift over

dbSNP: rs754673606; hg19: chr3-14190232; API