Genetic Variant NM_004628.5:c.1001C>A (chr3-14158882-G-T) – 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_004628.5(XPC):c.1001C>A(p.Pro334His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,613,868 control chromosomes in the GnomAD database, including 34 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. P334S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0075 ( 19 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 15 hom. )

Consequence

XPC
NM_004628.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.30

Publications

25 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=0.0046908855).

BP6

Variant 3-14158882-G-T is Benign according to our data. Variant chr3-14158882-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 253.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 = 0.00749 (1140/152194) while in subpopulation AFR AF = 0.0237 (983/41508). AF 95% confidence interval is 0.0225. There are 19 homozygotes in GnomAd4. There are 541 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

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.1001C>A	p.Pro334His	missense	Exon 9 of 16	NP_004619.3
XPC	NM_001354727.2		c.1001C>A	p.Pro334His	missense	Exon 9 of 16	NP_001341656.1	A0ABB0MVJ4
XPC	NM_001354729.2		c.983C>A	p.Pro328His	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.1001C>A	p.Pro334His	missense	Exon 9 of 16	ENSP00000285021.8	Q01831-1
XPC	ENST00000476581.6	TSL:1	n.*454C>A		non_coding_transcript_exon	Exon 8 of 15	ENSP00000424548.1	Q01831-3
XPC	ENST00000476581.6	TSL:1	n.*454C>A		3_prime_UTR	Exon 8 of 15	ENSP00000424548.1	Q01831-3

Frequencies

GnomAD3 genomes

AF:

0.00748

AC:

1137

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0237

Gnomad AMI

AF:

0.0286

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00258

AC:

637

AN:

247062

AF XY:

0.00200

show subpopulations

Gnomad AFR exome

AF:

0.0250

Gnomad AMR exome

AF:

0.00304

Gnomad ASJ exome

AF:

0.00835

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000352

Gnomad OTH exome

AF:

0.00364

GnomAD4 exome

AF:

0.00106

AC:

1554

AN:

1461674

Hom.:

Cov.:

AF XY:

0.000937

AC XY:

681

AN XY:

727120

show subpopulations

African (AFR)

AF:

0.0253

AC:

846

AN:

33480

American (AMR)

AF:

0.00335

AC:

150

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00758

AC:

198

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00261

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.000186

AC:

207

AN:

1111868

Other (OTH)

AF:

0.00225

AC:

136

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

186

280

373

466

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00749

AC:

1140

AN:

152194

Hom.:

Cov.:

AF XY:

0.00727

AC XY:

541

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.0237

AC:

983

AN:

41508

American (AMR)

AF:

0.00418

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00835

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68008

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

109

164

218

273

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:

0.00308

Hom.:

Bravo

AF:

0.00861

ESP6500AA

AF:

0.0268

AC:

ESP6500EA

AF:

0.000977

AC:

ExAC

AF:

0.00286

AC:

345

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000771

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Xeroderma pigmentosum, group C (5)

not provided (3)

not specified (2)

Xeroderma pigmentosum (1)

XPC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.27

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0047

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.5

PhyloP100

1.3

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.2

REVEL

Benign

0.078

Sift

Benign

0.10

Sift4G

Benign

0.10

Polyphen

0.85

Vest4

0.68

MVP

0.17

MPC

0.29

ClinPred

0.0062

GERP RS

3.1

Varity_R

0.085

gMVP

0.24

Mutation Taster

=87/13

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