Genetic Variant XPA:p.Met256Leu (chr9-97675495-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000380.4(XPA):c.766A>C(p.Met256Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M256V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

XPA
NM_000380.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.64

Publications

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

XPA links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13454646).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000380.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
XPA	NM_000380.4	MANE Select	c.766A>C	p.Met256Leu	missense	Exon 6 of 6	NP_000371.1	P23025
XPA	NM_001354975.2		c.640A>C	p.Met214Leu	missense	Exon 6 of 6	NP_001341904.1
XPA	NR_027302.2		n.1045A>C		non_coding_transcript_exon	Exon 7 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
XPA	ENST00000375128.5	TSL:1 MANE Select	c.766A>C	p.Met256Leu	missense	Exon 6 of 6	ENSP00000364270.5	P23025
XPA	ENST00000905837.1		c.499A>C	p.Met167Leu	missense	Exon 4 of 4	ENSP00000575896.1
XPA	ENST00000905836.1		c.376A>C	p.Met126Leu	missense	Exon 3 of 3	ENSP00000575895.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.15

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.66

M_CAP

Benign

0.0058

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.090

PhyloP100

2.6

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.50

REVEL

Benign

0.044

Sift

Benign

0.28

Sift4G

Benign

0.29

Polyphen

0.0010

Vest4

0.086

MutPred

0.22

Loss of disorder (P = 0.0781)

MVP

0.55

MPC

0.25

ClinPred

0.53

GERP RS

3.0

Varity_R

0.099

gMVP

0.19

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over