rs886063216

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000380.4(XPA):c.*77C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

XPA
NM_000380.4 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.818

Publications

1 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_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPA	NM_000380.4 link	c.*77C>A		3_prime_UTR_variant	Exon 6 of 6	ENST00000375128.5	NP_000371.1	P23025

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
XPA	ENST00000375128.5 link	c.*77C>A	3_prime_UTR_variant	Exon 6 of 6	1	NM_000380.4	ENSP00000364270.5	P23025
XPA	ENST00000462523.5 link	n.*335C>A	non_coding_transcript_exon_variant	Exon 7 of 7	5		ENSP00000433006.1	F2Z2T2
XPA	ENST00000485042.1 link	n.411C>A	non_coding_transcript_exon_variant	Exon 2 of 2	3
XPA	ENST00000462523.5 link	n.*335C>A	3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000433006.1	F2Z2T2

Frequencies

GnomAD3 genomes

AF:

0.000211

AC:

AN:

146984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000151

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000134

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000216

Gnomad FIN

AF:

0.00119

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000165

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000979

AC:

131

AN:

133810

AF XY:

0.000952

show subpopulations

Gnomad AFR exome

AF:

0.00199

Gnomad AMR exome

AF:

0.000130

Gnomad ASJ exome

AF:

0.00147

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.000614

Gnomad NFE exome

AF:

0.00146

Gnomad OTH exome

AF:

0.000882

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000175

AC:

214

AN:

1222054

Hom.:

Cov.:

AF XY:

0.000172

AC XY:

105

AN XY:

609002

show subpopulations

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

African (AFR)

AF:

0.00155

AC:

AN:

25862

American (AMR)

AF:

0.000368

AC:

AN:

24458

Ashkenazi Jewish (ASJ)

AF:

0.000455

AC:

AN:

21968

East Asian (EAS)

AF:

0.000145

AC:

AN:

34370

South Asian (SAS)

AF:

0.000146

AC:

AN:

68452

European-Finnish (FIN)

AF:

0.0000431

AC:

AN:

46430

Middle Eastern (MID)

AF:

0.000844

AC:

AN:

3554

European-Non Finnish (NFE)

AF:

0.000130

AC:

123

AN:

945794

Other (OTH)

AF:

0.000235

AC:

AN:

51166

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.301

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000211

AC:

AN:

146984

Hom.:

Cov.:

AF XY:

0.000224

AC XY:

AN XY:

71530

show subpopulations

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

African (AFR)

AF:

0.000151

AC:

AN:

39862

American (AMR)

AF:

0.000134

AC:

AN:

14890

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3414

East Asian (EAS)

AF:

0.00

AC:

AN:

5046

South Asian (SAS)

AF:

0.000216

AC:

AN:

4636

European-Finnish (FIN)

AF:

0.00119

AC:

AN:

9266

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000165

AC:

AN:

66628

Other (OTH)

AF:

0.00

AC:

AN:

2028

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.260

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00126

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Xeroderma pigmentosum group A

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.29

(source)

DANN

Benign

0.57

PhyloP100

-0.82

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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rs886063216

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over