ENST00000476581.6:n.*2409G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000476581.6(XPC):​n.*2409G>A 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 0.001 in 1,145,242 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00054 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 16 hom. )

Consequence

XPC
ENST00000476581.6 non_coding_transcript_exon

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.294

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-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 -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.87).
BP6
Variant 3-14145808-C-T is Benign according to our data. Variant chr3-14145808-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 343559.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=1}.
BS1
Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000538 (82/152288) while in subpopulation SAS AF = 0.0158 (76/4822). AF 95% confidence interval is 0.0129. There are 1 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
XPCNM_004628.5 linkc.*133G>A 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
XPCENST00000285021.12 linkc.*133G>A 3_prime_UTR_variant Exon 16 of 16 1 NM_004628.5 ENSP00000285021.8 Q01831-1
ENSG00000268279ENST00000608606.1 linkn.*198+125C>T intron_variant Intron 4 of 4 5 ENSP00000476275.1 V9GY05

Frequencies

GnomAD3 genomes
AF:
0.000545
AC:
83
AN:
152170
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000580
Gnomad SAS
AF:
0.0160
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000956
GnomAD2 exomes
AF:
0.00224
AC:
346
AN:
154570
AF XY:
0.00294
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000425
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000310
Gnomad OTH exome
AF:
0.00138
GnomAD4 exome
AF:
0.00107
AC:
1063
AN:
992954
Hom.:
16
Cov.:
13
AF XY:
0.00154
AC XY:
781
AN XY:
505844
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
23508
American (AMR)
AF:
0.0000286
AC:
1
AN:
34974
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
21878
East Asian (EAS)
AF:
0.000144
AC:
5
AN:
34638
South Asian (SAS)
AF:
0.0140
AC:
1001
AN:
71408
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
39674
Middle Eastern (MID)
AF:
0.000306
AC:
1
AN:
3268
European-Non Finnish (NFE)
AF:
0.0000167
AC:
12
AN:
718976
Other (OTH)
AF:
0.000963
AC:
43
AN:
44630
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
57
113
170
226
283
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome 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
GnomAD4 genome
AF:
0.000538
AC:
82
AN:
152288
Hom.:
1
Cov.:
32
AF XY:
0.000752
AC XY:
56
AN XY:
74450
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41572
American (AMR)
AF:
0.0000654
AC:
1
AN:
15302
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.000582
AC:
3
AN:
5158
South Asian (SAS)
AF:
0.0158
AC:
76
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10624
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68020
Other (OTH)
AF:
0.000946
AC:
2
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.504
Heterozygous variant carriers
0
4
8
13
17
21
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000128
Hom.:
0
Bravo
AF:
0.000140
Asia WGS
AF:
0.0150
AC:
52
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Xeroderma pigmentosum Uncertain:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
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

- -

Xeroderma pigmentosum, group C Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.87
CADD
Benign
1.8
DANN
Benign
0.55
PhyloP100
-0.29
Mutation Taster
=100/0
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: rs377250919; hg19: chr3-14187308; API