rs1324310300

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_000380.4(XPA):c.389G>A(p.Arg130Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000277 in 1,442,738 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: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

XPA
NM_000380.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 6.87

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

xeroderma pigmentosum group A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
xeroderma pigmentosum
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

XPA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 9-97689534-C-T is Pathogenic according to our data. Variant chr9-97689534-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 551153.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPA	NM_000380.4 link	c.389G>A	p.Arg130Lys	missense_variant, splice_region_variant	Exon 3 of 6	ENST00000375128.5	NP_000371.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
XPA	ENST00000375128.5 link	c.389G>A	p.Arg130Lys	missense_variant, splice_region_variant	Exon 3 of 6	1	NM_000380.4	ENSP00000364270.5
XPA	ENST00000462523.5 link	n.389G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 7	5		ENSP00000433006.1
XPA	ENST00000496104.1 link	n.184-2273G>A		intron_variant	Intron 2 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000277

AC:

AN:

1442738

Hom.:

Cov.:

AF XY:

0.00000556

AC XY:

AN XY:

719326

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33112

American (AMR)

AF:

0.00

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25994

East Asian (EAS)

AF:

0.00

AC:

AN:

39452

South Asian (SAS)

AF:

0.00

AC:

AN:

85846

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00000183

AC:

AN:

1094840

Other (OTH)

AF:

0.0000167

AC:

AN:

59714

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0188335), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.387

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.000156

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Xeroderma pigmentosum

Pathogenic:1

Jul 01, 2023

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Xeroderma pigmentosum group A

Uncertain:1

Mar 17, 2017

Counsyl

Significance:Uncertain significance

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.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.94

MetaSVM

Pathogenic

0.95

MutationAssessor

Benign

1.4

PhyloP100

6.9

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.7

REVEL

Pathogenic

0.71

Sift

Benign

0.18

Sift4G

Benign

0.26

Vest4

0.63

ClinPred

0.93

GERP RS

5.3

Varity_R

0.44

gMVP

0.69

Mutation Taster

=4/96

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.74

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.74

Position offset: 0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over