rs750218942

Positions:

chr9-97687262-C-G

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong

The NM_000380.4(XPA):c.390-1G>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000293 in 1,602,704 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

XPA
NM_000380.4 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 7.52

Variant links:

Genes affected

XPA (HGNC:12814): (XPA, DNA damage recognition and repair factor) This gene encodes a zinc finger protein plays a central role in nucleotide excision repair (NER), a specialized type of DNA repair. NER is responsible for repair of UV radiation-induced photoproducts and DNA adducts induced by chemical carcinogens and chemotherapeutic drugs. The encoded protein interacts with DNA and several NER proteins, acting as a scaffold to assemble the NER incision complex at sites of DNA damage. Mutations in this gene cause Xeroderma pigmentosum complementation group A (XP-A), an autosomal recessive skin disorder featuring hypersensitivity to sunlight and increased risk for skin cancer. [provided by RefSeq, Aug 2017]

XPA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 22 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 8.9, offset of 2, new splice context is: gacttaatctgttttcacAGatg. 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;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 9-97687262-C-G is Pathogenic according to our data. Variant chr9-97687262-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 264684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XPA	NM_000380.4 linkuse as main transcript	c.390-1G>C		splice_acceptor_variant		ENST00000375128.5

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris
XPA	ENST00000375128.5 linkuse as main transcript	c.390-1G>C	splice_acceptor_variant	1	NM_000380.4	P1
XPA	ENST00000462523.5 linkuse as main transcript	c.390-1G>C	splice_acceptor_variant, NMD_transcript_variant	5
XPA	ENST00000496104.1 linkuse as main transcript	n.184-1G>C	splice_acceptor_variant, non_coding_transcript_variant	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152146

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:

0.000192

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:

0.0000123

AC:

AN:

242978

Hom.:

AF XY:

0.00000760

AC XY:

AN XY:

131606

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000167

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:

0.0000317

AC:

AN:

1450558

Hom.:

Cov.:

AF XY:

0.0000264

AC XY:

AN XY:

720582

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00114

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Xeroderma pigmentosum group A

Pathogenic:5Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 26, 2017	The XPA c.390-1G>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The variant has been described as a founder variant in the Japanese population with a carrier frequency of approximately 0.9% (Hirai et al. 2006; Imoto et al. 2013). Across a selection of the available literature, the c.390-1G>C variant has been reported in 24 patients including 20 patients with the variant in a homozygous state and four in a heterozygous state (Satokata et al. 1990; Sun et al. 2015; Choi et al. 2016; Zhou et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.00037 in the East Asian population of the Exome Aggregation Consortium. The c.390-1G>C variant affects splicing, creating two abnormally spliced mRNA forms, both of which result in premature truncation of the protein (Satokata et al. 1990). Based on the collective evidence and the potential impact of splice acceptor variants, the c.390-1G>C variant is classified as pathogenic for xeroderma pigmentosum. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 03, 2021	NM_000380.3(XPA):c.390-1G>C is a canonical splice variant classified as pathogenic in the context of xeroderma pigmentosum group A. c.390-1G>C has been observed in cases with relevant disease (PMID: 1702221, 7577588). Functional assessments of this variant are available in the literature (PMID: 1702221). c.390-1G>C has been observed in population frequency databases (gnomAD: EAS 0.02%). In summary, NM_000380.3(XPA):c.390-1G>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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Canonical splice site: predicted to alter splicing and 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).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.00001235, PM2). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000264684.5). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 09, 2024	- -

Xeroderma pigmentosum

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 20, 2020

Variant summary: XPA c.390-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site and creates/strengthens a cryptic exonic one. Experimental evidence supports these predictions demonstrating the variant results in the production of aberrant mRNA transcripts (Satokata_1990). The variant allele was found at a frequency of 1.2e-05 in 242978 control chromosomes (gnomAD). c.390-1G>C is described in the literature as a founder mutation in the Japanese population and has been reported in multiple individuals affected with Xeroderma Pigmentosum (e.g. Satokata_1990, Hirai_2006, Imoto_2013). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 21, 2023

This sequence change affects an acceptor splice site in intron 3 of the XPA 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 (rs750218942, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with xeroderma pigmentosum (PMID: 27607234). It is commonly reported in individuals of Japanese ancestry (PMID: 2234061, 23194742). ClinVar contains an entry for this variant (Variation ID: 264684). Studies have shown that disruption of this splice site results in activation of a cryptic splice site in exon 4 and introduces a premature termination codon (PMID: 1702221). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

GERP RS

5.3

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.99

Position offset: -3

DS_AL_spliceai

0.82

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.

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