rs1451780491

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000380.4(XPA):c.378T>G(p.Cys126Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,457,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

XPA
NM_000380.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2U:1

Conservation

PhyloP100: 1.77

Publications

3 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: Pathogenic. The variant received 16 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity XPA_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.995

PP5

Variant 9-97689545-A-C is Pathogenic according to our data. Variant chr9-97689545-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 553368.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
XPA	NM_000380.4 link	c.378T>G	p.Cys126Trp	missense_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.378T>G	p.Cys126Trp	missense_variant	Exon 3 of 6	1	NM_000380.4	ENSP00000364270.5
XPA	ENST00000462523.5 link	n.378T>G		non_coding_transcript_exon_variant	Exon 3 of 7	5		ENSP00000433006.1
XPA	ENST00000496104.1 link	n.184-2284T>G		intron_variant	Intron 2 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250836

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1457384

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725420

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33390

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.00

AC:

AN:

39546

South Asian (SAS)

AF:

0.00

AC:

AN:

86118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000361

AC:

AN:

1108194

Other (OTH)

AF:

0.00

AC:

AN:

60216

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.0000282

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Xeroderma pigmentosum

Pathogenic:2

Dec 29, 2021

Sema4, Sema4

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Aug 01, 2023

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: XPA c.378T>G (p.Cys126Trp) results in a non-conservative amino acid change located in the zinc finger domain (IPR022652), affecting a zinc-coordinating Cys residue (PMID 9078375) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250836 control chromosomes (gnomAD). c.378T>G has been reported in the literature in at least one homozygous individual affected with Xeroderma Pigmentosum (Tamhankar_2015). These data indicate that the variant may be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant drastically reduces nucleotide excision repair (NER) in a cell-based NER activity assay (Blee_2022). The following publications have been ascertained in the context of this evaluation (PMID: 35687855, 25566891). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Xeroderma pigmentosum group A

Uncertain:1

Aug 16, 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.89

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

PhyloP100

1.8

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-11

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MutPred

0.95

Loss of disorder (P = 0.054);

MVP

0.99

MPC

1.1

ClinPred

1.0

GERP RS

2.9

Varity_R

0.99

gMVP

0.93

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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