chr3-14158882-G-T

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

18

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

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 [Likely_benign]. Clinvar id 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

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
XPCNM_004628.5 linkc.1001C>A p.Pro334His missense_variant Exon 9 of 16 ENST00000285021.12 NP_004619.3 Q01831-1X5DRB1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
XPCENST00000285021.12 linkc.1001C>A p.Pro334His missense_variant Exon 9 of 16 1 NM_004628.5 ENSP00000285021.8 Q01831-1

Frequencies

GnomAD3 genomes
AF:
0.00748
AC:
1137
AN:
152076
Hom.:
19
Cov.:
32
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.:
15
Cov.:
32
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:
0
AN:
39700
South Asian (SAS)
AF:
0.0000232
AC:
2
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53394
Middle Eastern (MID)
AF:
0.00261
AC:
15
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
0
93
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
0
34
68
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.:
19
Cov.:
32
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:
64
AN:
15294
Ashkenazi Jewish (ASJ)
AF:
0.00835
AC:
29
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5174
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4814
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10606
Middle Eastern (MID)
AF:
0.00680
AC:
2
AN:
294
European-Non Finnish (NFE)
AF:
0.000382
AC:
26
AN:
68008
Other (OTH)
AF:
0.00473
AC:
10
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
55
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
0
20
40
60
80
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.:
6
Bravo
AF:
0.00861
ESP6500AA
AF:
0.0268
AC:
84
ESP6500EA
AF:
0.000977
AC:
7
ExAC
AF:
0.00286
AC:
345
Asia WGS
AF:
0.00144
AC:
5
AN:
3478
EpiCase
AF:
0.000273
EpiControl
AF:
0.000771

ClinVar

Significance: Benign/Likely benign
Submissions summary: Pathogenic:1Uncertain:1Benign:9Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Xeroderma pigmentosum, group C Pathogenic:1Uncertain:1Benign:3
Dec 01, 1993
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Aug 22, 2023
Mendelics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Sep 01, 2020
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:research

- -

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jan 06, 2020
Reproductive Health Research and Development, BGI Genomics
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:curation

NM_004628.4:c.1001C>A (p.Pro334His) was previously reported as P218H. This variant has an allele frequency of 0.026 in African subpopulation in the gnomAD database. It has been reported previously in individuals with Xeroderma Pigmentosum in homozygous state (PMID: 17079196, 17084680). Functional studies show p.Pro334His mutation prevents the stimulation of Ogg1 glycosylase because it thwarts the interaction between XPC and Ogg1 (PMID: 18809580). Benign computational verdict because benign predictions from DEOGEN2, EIGEN, FATHMM-MKL, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT vs 1 pathogenic prediction from DANN and the position is not conserved. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: BS1, BP4, BP1, PS3, PM3_Supporting. -

not provided Benign:3
Sep 27, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

XPC: BP4, BS1, BS2 -

Dec 18, 2019
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 18955168, 8298653, 25333069, 17079196, 29973595, 30516811, 30675318, 31816862, 24728327, 18809580, 30256826, 27153395) -

not specified Benign:1Other:1
Sep 19, 2013
ITMI
Significance:not provided
Review Status:no classification provided
Collection Method:reference population

- -

Feb 18, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: XPC c.1001C>A (p.Pro334His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0026 in 247062 control chromosomes, predominantly at a frequency of 0.025 within the African or African-American subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 35 fold of the estimated maximal expected allele frequency for a pathogenic variant in XPC causing Xeroderma Pigmentosum phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1001C>A has been reported in the literature (example, Bonache_2018, Li_1993, Martin-Morales_2018, Maxwell_2016, Pugh_2019, Ramirez-Calvo_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Xeroderma Pigmentosum. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (example, BernardesdeJesus_2008, Bidon_2018). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Xeroderma pigmentosum Benign:1
Mar 26, 2020
Sema4, Sema4
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:curation

- -

XPC-related disorder Benign:1
Apr 10, 2021
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.099
BayesDel_addAF
Benign
-0.50
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
18
DANN
Benign
0.95
DEOGEN2
Benign
0.27
T
Eigen
Benign
-0.42
Eigen_PC
Benign
-0.51
FATHMM_MKL
Benign
0.23
N
LIST_S2
Benign
0.61
T
MetaRNN
Benign
0.0047
T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
1.5
L
PhyloP100
1.3
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-1.2
N
REVEL
Benign
0.078
Sift
Benign
0.10
T
Sift4G
Benign
0.10
T
Polyphen
0.85
P
Vest4
0.68
MVP
0.17
MPC
0.29
ClinPred
0.0062
T
GERP RS
3.1
Varity_R
0.085
gMVP
0.24
Mutation Taster
=87/13
polymorphism

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

Other links and lift over

dbSNP: rs74737358; hg19: chr3-14200382; COSMIC: COSV99034868; API