dbSNP rs2125004457: XPC:p.Glu938Asp (chr3-14145950-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004628.5(XPC):c.2814G>C(p.Glu938Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E938E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

XPC
NM_004628.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.57

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19601125).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPC	NM_004628.5 link	c.2814G>C	p.Glu938Asp	missense_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
XPC	ENST00000285021.12 link	c.2814G>C	p.Glu938Asp	missense_variant	Exon 16 of 16	1	NM_004628.5	ENSP00000285021.8		Q01831-1
ENSG00000268279	ENST00000608606.1 link	n.*198+267C>G		intron_variant	Intron 4 of 4	5		ENSP00000476275.1		V9GY05

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1452682

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720842

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33180

American (AMR)

AF:

0.00

AC:

AN:

44316

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25978

East Asian (EAS)

AF:

0.00

AC:

AN:

39438

South Asian (SAS)

AF:

0.00

AC:

AN:

85942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53156

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5648

European-Non Finnish (NFE)

AF:

9.05e-7

AC:

AN:

1105118

Other (OTH)

AF:

0.00

AC:

AN:

59906

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.77

M_CAP

Benign

0.040

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.6

PhyloP100

1.6

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.2

REVEL

Benign

0.15

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.38

MutPred

0.16

Loss of MoRF binding (P = 0.1308);

MVP

0.45

MPC

0.54

ClinPred

0.98

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.67

gMVP

0.23

Mutation Taster

=73/27

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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rs2125004457

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over