dbSNP rs3176750: XPA:p.Leu252Val (chr9-97675507-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000380.4(XPA):c.754C>G(p.Leu252Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,613,834 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L252L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0099 ( 25 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 12 hom. )

Consequence

XPA
NM_000380.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -0.0560

Publications

12 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: Myriad Women’s Health, ClinGen, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017201304).

BP6

Variant 9-97675507-G-C is Benign according to our data. Variant chr9-97675507-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00986 (1499/152084) while in subpopulation AFR AF = 0.0334 (1385/41492). AF 95% confidence interval is 0.0319. There are 25 homozygotes in GnomAd4. There are 701 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 AR gene

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.754C>G	p.Leu252Val	missense	Exon 6 of 6	NP_000371.1	P23025
XPA	NM_001354975.2		c.628C>G	p.Leu210Val	missense	Exon 6 of 6	NP_001341904.1
XPA	NR_027302.2		n.1033C>G		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.754C>G	p.Leu252Val	missense	Exon 6 of 6	ENSP00000364270.5	P23025
XPA	ENST00000905837.1		c.487C>G	p.Leu163Val	missense	Exon 4 of 4	ENSP00000575896.1
XPA	ENST00000905836.1		c.364C>G	p.Leu122Val	missense	Exon 3 of 3	ENSP00000575895.1

Frequencies

GnomAD3 genomes

AF:

0.00985

AC:

1497

AN:

151966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0334

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00498

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00861

GnomAD2 exomes

AF:

0.00286

AC:

718

AN:

251250

AF XY:

0.00210

show subpopulations

Gnomad AFR exome

AF:

0.0359

Gnomad AMR exome

AF:

0.00287

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.000997

AC:

1458

AN:

1461750

Hom.:

Cov.:

AF XY:

0.000869

AC XY:

632

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.0313

AC:

1047

AN:

33474

American (AMR)

AF:

0.00271

AC:

121

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000133

AC:

148

AN:

1111940

Other (OTH)

AF:

0.00214

AC:

129

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

168

251

335

419

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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

AF:

0.00986

AC:

1499

AN:

152084

Hom.:

Cov.:

AF XY:

0.00943

AC XY:

701

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.0334

AC:

1385

AN:

41492

American (AMR)

AF:

0.00498

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000208

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10556

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

67992

Other (OTH)

AF:

0.00852

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

144

215

287

359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00182

Hom.:

Bravo

AF:

0.0109

ESP6500AA

AF:

0.0327

AC:

144

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00331

AC:

402

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Xeroderma pigmentosum group A (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.62

CADD

Benign

9.0

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.093

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.0

PhyloP100

-0.056

PrimateAI

Benign

0.25

PROVEAN

Benign

0.41

REVEL

Benign

0.034

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0030

Vest4

0.048

MVP

0.39

MPC

0.27

ClinPred

0.0028

GERP RS

-4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.051

gMVP

0.13

Mutation Taster

=92/8

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over