rs975121308

Variant names:

• chr3-14165427-C-A
• rs975121308
• NM_004628.5:c.779+1G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-14165427-C-A
• chr3-14165427-C-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004628.5(XPC):​c.779+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000252 in 1,588,782 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: XPC NM_004628.5 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.62
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-14165427-C-A is Pathogenic according to our data. Variant chr3-14165427-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14165427-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14165427-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14165427-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14165427-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14165427-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14165427-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14165427-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14165427-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14165427-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14165427-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14165427-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14165427-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14165427-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14165427-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 554889.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
XPC	NM_004628.5	c.779+1G>T		splice_donor_variant, intron_variant	Intron 6 of 15	ENST00000285021.12	NP_004619.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPC	ENST00000285021.12	c.779+1G>T		splice_donor_variant, intron_variant	Intron 6 of 15	1	NM_004628.5	ENSP00000285021.8

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 215586 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000209 AC: 3 AN: 1436560 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 711598

African (AFR) AF: 0.00 AC: 0 AN: 32964

American (AMR) AF: 0.00 AC: 0 AN: 41400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25654

East Asian (EAS) AF: 0.00 AC: 0 AN: 38716

South Asian (SAS) AF: 0.00 AC: 0 AN: 82338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5184

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1098832

Other (OTH) AF: 0.00 AC: 0 AN: 59468

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum, group C Pathogenic:2

Dec 27, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 08, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided Pathogenic:2

Jan 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 6 of the XPC gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in XPC are known to be pathogenic (PMID: 23173980, 25256075). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with xeroderma pigmentosum (PMID: 23984341; Invitae). ClinVar contains an entry for this variant (Variation ID: 554889). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Aug 18, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		6.6
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.95		Position offset: 9
DS_DL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs975121308; hg19: chr3-14206927;