rs752088918
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004628.5(XPC):c.566_567delAT(p.Tyr189SerfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,611,056 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )
Consequence
XPC
NM_004628.5 frameshift
NM_004628.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.49
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]
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 3-14167222-GAT-G is Pathogenic according to our data. Variant chr3-14167222-GAT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152176Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
3
AN:
152176
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000243 AC: 6AN: 246448Hom.: 0 AF XY: 0.00000747 AC XY: 1AN XY: 133816
GnomAD3 exomes
AF:
AC:
6
AN:
246448
Hom.:
AF XY:
AC XY:
1
AN XY:
133816
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1458880Hom.: 0 AF XY: 0.0000152 AC XY: 11AN XY: 725670
GnomAD4 exome
AF:
AC:
25
AN:
1458880
Hom.:
AF XY:
AC XY:
11
AN XY:
725670
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74330
GnomAD4 genome
AF:
AC:
3
AN:
152176
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74330
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Xeroderma pigmentosum, group C Pathogenic:5
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 13, 2025 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2000 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 19, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 06, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 30, 2024 | - - |
Xeroderma pigmentosum Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 20, 2017 | Variant summary: The c.566_567delAT (p.Tyr189Serfs) variant in XPC gene is a frameshift change predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. These predictions were confirmed by Northern blot analysis that has revealed greatly reduced xeroderma pigmentosum complementation group C mRNA as well as reductions in post-ultraviolet survival rate, unscheduled DNA synthesis, global genome DNA repair deficiency and aborted plasmid host cell reactivation (Slor ,2000). The variant is present in the large control population dataset of ExAC at a low frequency 0.00004 (5/113986 chrs tested), exclusively in individuals of European descent (0.000079; 5/63374 chrs tested) which does not exceed the maximal expected frequency of a pathogenic allele (0.0014) in this gene. The variant of interest has been reported homozygously in at least 3 XP-C patients. The c.566_567delAT is cited as Pathogenic by reputable database/diagnostic center. Taken together, the variant was classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 02, 2024 | This sequence change creates a premature translational stop signal (p.Tyr189Serfs*10) 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 (rs752088918, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with xeroderma pigmentosum (PMID: 11121128). It has also been observed to segregate with disease in related individuals. This variant is also known as c.669_670delAT. ClinVar contains an entry for this variant (Variation ID: 258). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at