rs3731178

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The ENST00000476581.6(XPC):n.*2468T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 738,870 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.010 ( 28 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 13 hom. )

Consequence

XPC
ENST00000476581.6 non_coding_transcript_exon

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.301

Publications

0 publications found

Variant links:

Genes affected

XPC (HGNC:12816): (XPC complex subunit, DNA damage recognition and repair factor) The protein encoded by this gene is a key component of the XPC complex, which plays an important role in the early steps of global genome nucleotide excision repair (NER). The encoded protein is important for damage sensing and DNA binding, and shows a preference for single-stranded DNA. Mutations in this gene or some other NER components can result in Xeroderma pigmentosum, a rare autosomal recessive disorder characterized by increased sensitivity to sunlight with the development of carcinomas at an early age. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2017]

XPC links:

ENSG00000268279 (HGNC:):

ENSG00000268279 links:

XPC-AS1 (HGNC:55014): (XPC antisense RNA 1)

XPC-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.01 (1527/152280) while in subpopulation AFR AF = 0.0345 (1435/41538). AF 95% confidence interval is 0.0331. There are 28 homozygotes in GnomAd4. There are 727 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPC	NM_004628.5 link	c.*192T>C		3_prime_UTR_variant	Exon 16 of 16	ENST00000285021.12	NP_004619.3	Q01831-1X5DRB1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPC	ENST00000285021.12 link	c.*192T>C		3_prime_UTR_variant	Exon 16 of 16	1	NM_004628.5	ENSP00000285021.8		Q01831-1
ENSG00000268279	ENST00000608606.1 link	n.*198+66A>G		intron_variant	Intron 4 of 4	5		ENSP00000476275.1		V9GY05

Frequencies

GnomAD3 genomes

AF:

0.0100

AC:

1528

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0347

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00477

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00228

AC:

308

AN:

134806

AF XY:

0.00190

show subpopulations

Gnomad AFR exome

AF:

0.0379

Gnomad AMR exome

AF:

0.00175

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000572

Gnomad OTH exome

AF:

0.00123

GnomAD4 exome

AF:

0.00128

AC:

752

AN:

586590

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

335

AN XY:

315364

show subpopulations

African (AFR)

AF:

0.0363

AC:

595

AN:

16396

American (AMR)

AF:

0.00196

AC:

AN:

34738

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20190

East Asian (EAS)

AF:

0.00

AC:

AN:

32218

South Asian (SAS)

AF:

0.0000639

AC:

AN:

62640

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33700

Middle Eastern (MID)

AF:

0.000792

AC:

AN:

2524

European-Non Finnish (NFE)

AF:

0.0000284

AC:

AN:

352468

Other (OTH)

AF:

0.00230

AC:

AN:

31716

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

147

196

245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0100

AC:

1527

AN:

152280

Hom.:

Cov.:

AF XY:

0.00976

AC XY:

727

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0345

AC:

1435

AN:

41538

American (AMR)

AF:

0.00477

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68026

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

147

220

294

367

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00443

Hom.:

Bravo

AF:

0.0118

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Xeroderma pigmentosum

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Feb 28, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Xeroderma pigmentosum, group C

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

6.4

(source)

DANN

Benign

0.64

PhyloP100

-0.30

Mutation Taster

=100/0

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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rs3731178

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