rs746617574

Positions:

chr9-97687096-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000380.4(XPA):c.555G>C(p.Gln185His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000821 in 1,608,286 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 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000089 ( 0 hom. )

Consequence

XPA
NM_000380.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

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 14 ACMG points.

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 9-97687096-C-G is Pathogenic according to our data. Variant chr9-97687096-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XPA	NM_000380.4 linkuse as main transcript	c.555G>C	p.Gln185His	missense_variant, splice_region_variant	4/6	ENST00000375128.5	NP_000371.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
XPA	ENST00000375128.5 linkuse as main transcript	c.555G>C	p.Gln185His	missense_variant, splice_region_variant	4/6	1	NM_000380.4	ENSP00000364270	P1
XPA	ENST00000496104.1 linkuse as main transcript	n.349G>C		splice_region_variant, non_coding_transcript_exon_variant	3/4	3
XPA	ENST00000462523.5 linkuse as main transcript	c.555G>C	p.Gln185His	missense_variant, splice_region_variant, NMD_transcript_variant	4/7	5		ENSP00000433006

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152084

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

247850

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

133904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000886

AC:

129

AN:

1456202

Hom.:

Cov.:

AF XY:

0.0000856

AC XY:

AN XY:

724090

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000114

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Xeroderma pigmentosum group A

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 12, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 07, 2017	- -

XPA-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 13, 2023

The XPA c.555G>C variant is predicted to result in the amino acid substitution p.Gln185His. This variant has been reported in the homozygous and compound heterozygous states in individuals with Xeroderma pigmentosum (Satokata et al. 1992. PubMed ID: 1372103; States et al. 1996. PubMed ID: 8765158). This variant is also at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. Functional studies showed that this variant affects XPA function (Satokata et al. 1992. PubMed ID: 1372103; States et al. 1996. PubMed ID: 8765158; Nagel et al. 2014. PubMed ID: 24757057). This variant is reported in 0.0027% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-100449378-C-G). This variant is interpreted as likely pathogenic. -

Xeroderma pigmentosum

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 18, 2022

Variant summary: XPA c.555G>C (p.Gln185His) results in a non-conservative amino acid change located in the C-terminal domain (IPR022656) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. This variant also affects the last nucleotide of exon 4, and therefore could affect splicing: one computational tool predicts a significant impact on normal splicing, indicating that the variant abolishes a canonical 5' splicing donor site. Publications have reported experimental evidence confirming that this variant indeed affects mRNA splicing (e.g. Satokata_1992, States_1996, Nagel_2014).The variant allele was found at a frequency of 1.2e-05 in 247850 control chromosomes, exclusively within the European (non-Finnish) subpopulation (i.e. 3/112734 alleles) in the gnomAD database. c.555G>C has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Xeroderma pigmentosum, who were all of Caucasian ancestry, and generally had milder skin symptoms and absent or delayed-onset neurological disease (e.g. Satokata_1992, States_1996, States_1998). These data indicate that the variant is very likely to be associated with disease. Several publications reported experimental evidence evaluating the variant, and demonstrated that almost no correctly spliced mRNA was detected, and some mRNAs with in-frame insertions or deletions were also generated that theoretically could produce functional proteins (e.g. Satokata_1992, States_1996, Nagel_2014). This was consistent with a somewhat preserved UV-resistance of a patient-derived cell line that was homozygous for the variant of interest, and might also explain the milder clinical phenotypes reported in patients (Satokata_1992). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Both laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 26, 2023

This sequence change affects codon 185 of the XPA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the XPA protein. This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is present in population databases (rs746617574, gnomAD 0.003%). This variant has been observed in individual(s) with clinical features of XPA-related conditions (PMID: 1372103). ClinVar contains an entry for this variant (Variation ID: 550646). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this variant affects XPA function (PMID: 24757057). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 1372103). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

-0.054

MutationAssessor

Pathogenic

3.3

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.0

REVEL

Uncertain

0.64

Sift

Uncertain

0.029

Sift4G

Pathogenic

0.0

Polyphen

0.49

Vest4

0.90

MutPred

0.69

Loss of stability (P = 0.1207);

MVP

0.89

MPC

0.86

ClinPred

0.96

GERP RS

5.6

Varity_R

0.83

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.96

SpliceAI score (max)

0.69

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.69

Position offset: 0

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