Genetic Variant NM_004628.5:c.*624A>C (chr3-14145317-T-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_004628.5(XPC):c.*624A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000521 in 697,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

XPC
NM_004628.5 3_prime_UTR

Scores

Splicing: ADA: 0.001800

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.758

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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00129 (196/152228) while in subpopulation AFR AF = 0.00417 (173/41526). AF 95% confidence interval is 0.00366. There are 0 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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	Effect	Exon Rank	Protein	UniProt
XPC	NM_004628.5	MANE Select	c.*624A>C	3_prime_UTR	Exon 16 of 16	NP_004619.3
XPC	NM_001354727.2		c.*624A>C	3_prime_UTR	Exon 16 of 16	NP_001341656.1	A0ABB0MVJ4
XPC	NM_001354729.2		c.*624A>C	3_prime_UTR	Exon 16 of 16	NP_001341658.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
XPC	ENST00000285021.12	TSL:1 MANE Select	c.*624A>C	3_prime_UTR	Exon 16 of 16	ENSP00000285021.8	Q01831-1
ENSG00000268279	ENST00000608606.1	TSL:5	n.236-5T>G	splice_region intron	N/A	ENSP00000476275.1	V9GY05
XPC	ENST00000850575.1		c.*624A>C	3_prime_UTR	Exon 16 of 16	ENSP00000520865.1	A0ABB0MVJ4

Frequencies

GnomAD3 genomes

AF:

0.00129

AC:

196

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00418

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000378

AC:

AN:

127124

AF XY:

0.000260

show subpopulations

Gnomad AFR exome

AF:

0.00364

Gnomad AMR exome

AF:

0.000339

Gnomad ASJ exome

AF:

0.000251

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000749

Gnomad NFE exome

AF:

0.000164

Gnomad OTH exome

AF:

0.00101

GnomAD4 exome

AF:

0.000306

AC:

167

AN:

544926

Hom.:

Cov.:

AF XY:

0.000217

AC XY:

AN XY:

294926

show subpopulations

African (AFR)

AF:

0.00488

AC:

AN:

15562

American (AMR)

AF:

0.000382

AC:

AN:

33998

Ashkenazi Jewish (ASJ)

AF:

0.000201

AC:

AN:

19930

East Asian (EAS)

AF:

0.00

AC:

AN:

32096

South Asian (SAS)

AF:

0.00

AC:

AN:

61524

European-Finnish (FIN)

AF:

0.000693

AC:

AN:

33174

Middle Eastern (MID)

AF:

0.000822

AC:

AN:

2432

European-Non Finnish (NFE)

AF:

0.0000855

AC:

AN:

315880

Other (OTH)

AF:

0.000725

AC:

AN:

30330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00129

AC:

196

AN:

152228

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00417

AC:

173

AN:

41526

American (AMR)

AF:

0.000589

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68018

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000854

Hom.:

Bravo

AF:

0.00169

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Xeroderma pigmentosum, group C (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

8.0

(source)

DANN

Benign

0.71

PhyloP100

0.76

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0018

dbscSNV1_RF

Benign

0.026

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.22

Position offset: 5

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