chr3-14158408-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004628.5(XPC):c.1475G>A(p.Arg492His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0504 in 1,613,866 control chromosomes in the GnomAD database, including 2,337 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R492C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.040 ( 167 hom., cov: 32)

Exomes 𝑓: 0.052 ( 2170 hom. )

Consequence

XPC
NM_004628.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: -0.190

Publications

32 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:

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001995474).

BP6

Variant 3-14158408-C-T is Benign according to our data. Variant chr3-14158408-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0569 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004628.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
XPC	NM_004628.5	MANE Select	c.1475G>A	p.Arg492His	missense	Exon 9 of 16	NP_004619.3
XPC	NM_001354727.2		c.1475G>A	p.Arg492His	missense	Exon 9 of 16	NP_001341656.1	A0ABB0MVJ4
XPC	NM_001354729.2		c.1457G>A	p.Arg486His	missense	Exon 9 of 16	NP_001341658.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
XPC	ENST00000285021.12	TSL:1 MANE Select	c.1475G>A	p.Arg492His	missense	Exon 9 of 16	ENSP00000285021.8	Q01831-1
XPC	ENST00000476581.6	TSL:1	n.*928G>A		non_coding_transcript_exon	Exon 8 of 15	ENSP00000424548.1	Q01831-3
XPC	ENST00000476581.6	TSL:1	n.*928G>A		3_prime_UTR	Exon 8 of 15	ENSP00000424548.1	Q01831-3

Frequencies

GnomAD3 genomes

AF:

0.0397

AC:

6037

AN:

152088

Hom.:

167

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0109

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0459

Gnomad ASJ

AF:

0.0763

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.0358

Gnomad FIN

AF:

0.0295

Gnomad MID

AF:

0.0318

Gnomad NFE

AF:

0.0584

Gnomad OTH

AF:

0.0612

GnomAD2 exomes

AF:

0.0421

AC:

10493

AN:

249056

AF XY:

0.0435

show subpopulations

Gnomad AFR exome

AF:

0.0100

Gnomad AMR exome

AF:

0.0313

Gnomad ASJ exome

AF:

0.0687

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.0272

Gnomad NFE exome

AF:

0.0572

Gnomad OTH exome

AF:

0.0473

GnomAD4 exome

AF:

0.0515

AC:

75295

AN:

1461660

Hom.:

2170

Cov.:

AF XY:

0.0513

AC XY:

37310

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.00887

AC:

297

AN:

33480

American (AMR)

AF:

0.0327

AC:

1463

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0679

AC:

1775

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0402

AC:

3466

AN:

86258

European-Finnish (FIN)

AF:

0.0284

AC:

1518

AN:

53384

Middle Eastern (MID)

AF:

0.0517

AC:

298

AN:

5768

European-Non Finnish (NFE)

AF:

0.0572

AC:

63647

AN:

1111844

Other (OTH)

AF:

0.0468

AC:

2827

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

5033

10067

15100

20134

25167

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2298

4596

6894

9192

11490

<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:

0.0397

AC:

6036

AN:

152206

Hom.:

167

Cov.:

AF XY:

0.0395

AC XY:

2938

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0109

AC:

453

AN:

41532

American (AMR)

AF:

0.0459

AC:

702

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0763

AC:

265

AN:

3472

East Asian (EAS)

AF:

0.000388

AC:

AN:

5156

South Asian (SAS)

AF:

0.0354

AC:

171

AN:

4826

European-Finnish (FIN)

AF:

0.0295

AC:

313

AN:

10608

Middle Eastern (MID)

AF:

0.0342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0584

AC:

3974

AN:

67998

Other (OTH)

AF:

0.0601

AC:

127

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

283

566

850

1133

1416

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

216

288

360

<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:

0.0517

Hom.:

617

Bravo

AF:

0.0384

TwinsUK

AF:

0.0491

AC:

182

ALSPAC

AF:

0.0560

AC:

216

ESP6500AA

AF:

0.0128

AC:

ESP6500EA

AF:

0.0613

AC:

439

ExAC

AF:

0.0423

AC:

5109

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0566

EpiControl

AF:

0.0567

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Xeroderma pigmentosum, group C (3)

not specified (2)

Xeroderma pigmentosum group A (1)

XPC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.60

CADD

Benign

1.5

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.11

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.27

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

-0.19

PrimateAI

Benign

0.20

PROVEAN

Benign

-1.1

REVEL

Benign

0.012

Sift

Benign

0.23

Sift4G

Benign

0.11

Polyphen

0.0

Vest4

0.011

MPC

0.15

ClinPred

0.0042

GERP RS

-4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.014

gMVP

0.12

Mutation Taster

=99/1

polymorphism (auto)

(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