rs1870134

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004628.5(XPC):c.46C>G(p.Leu16Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0165 in 1,612,914 control chromosomes in the GnomAD database, including 1,591 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 209 hom., cov: 33)

Exomes 𝑓: 0.016 ( 1382 hom. )

Consequence

XPC
NM_004628.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: -1.25

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032751262).

BP6

Variant 3-14178523-G-C is Benign according to our data. Variant chr3-14178523-G-C is described in ClinVar as [Benign]. Clinvar id is 135465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XPC	NM_004628.5 linkuse as main transcript	c.46C>G	p.Leu16Val	missense_variant	1/16	ENST00000285021.12	NP_004619.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPC	ENST00000285021.12 linkuse as main transcript	c.46C>G	p.Leu16Val	missense_variant	1/16	1	NM_004628.5	ENSP00000285021	P1	Q01831-1
XPC	ENST00000476581.6 linkuse as main transcript	c.46C>G	p.Leu16Val	missense_variant, NMD_transcript_variant	1/15	1		ENSP00000424548		Q01831-3
XPC	ENST00000511155.1 linkuse as main transcript	c.46C>G	p.Leu16Val	missense_variant	1/4	4		ENSP00000423867

Frequencies

GnomAD3 genomes

AF:

0.0220

AC:

3353

AN:

152266

Hom.:

208

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00492

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0917

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.216

Gnomad SAS

AF:

0.0374

Gnomad FIN

AF:

0.00828

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00441

Gnomad OTH

AF:

0.0191

GnomAD3 exomes

AF:

0.0419

AC:

10341

AN:

246582

Hom.:

771

AF XY:

0.0372

AC XY:

5000

AN XY:

134300

show subpopulations

Gnomad AFR exome

AF:

0.00416

Gnomad AMR exome

AF:

0.126

Gnomad ASJ exome

AF:

0.00361

Gnomad EAS exome

AF:

0.225

Gnomad SAS exome

AF:

0.0284

Gnomad FIN exome

AF:

0.0105

Gnomad NFE exome

AF:

0.00507

Gnomad OTH exome

AF:

0.0321

GnomAD4 exome

AF:

0.0159

AC:

23236

AN:

1460530

Hom.:

1382

Cov.:

AF XY:

0.0158

AC XY:

11494

AN XY:

726614

show subpopulations

Gnomad4 AFR exome

AF:

0.00365

Gnomad4 AMR exome

AF:

0.122

Gnomad4 ASJ exome

AF:

0.00395

Gnomad4 EAS exome

AF:

0.215

Gnomad4 SAS exome

AF:

0.0300

Gnomad4 FIN exome

AF:

0.0115

Gnomad4 NFE exome

AF:

0.00401

Gnomad4 OTH exome

AF:

0.0221

GnomAD4 genome

AF:

0.0221

AC:

3361

AN:

152384

Hom.:

209

Cov.:

AF XY:

0.0252

AC XY:

1880

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.00493

Gnomad4 AMR

AF:

0.0918

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.217

Gnomad4 SAS

AF:

0.0374

Gnomad4 FIN

AF:

0.00828

Gnomad4 NFE

AF:

0.00442

Gnomad4 OTH

AF:

0.0203

Alfa

AF:

0.00496

Hom.:

Bravo

AF:

0.0291

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.00434

AC:

ESP6500EA

AF:

0.00522

AC:

ExAC

AF:

0.0369

AC:

4455

Asia WGS

AF:

0.117

AC:

407

AN:

3478

EpiCase

AF:

0.00431

EpiControl

AF:

0.00450

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	Claritas Genomics	Jun 20, 2012	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 16, 2021	Variant summary: XPC c.46C>G (p.Leu16Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.042 in 246582 control chromosomes in the gnomAD database, including 771 homozygotes. The observed variant frequency is approximately 59-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 benign. To our knowledge, no occurrence of c.46C>G in individuals affected with Xeroderma Pigmentosum and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Xeroderma pigmentosum, group C

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Xeroderma pigmentosum group A

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.13

DANN

Benign

0.63

DEOGEN2

Benign

0.051

T;T

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.26

T;T

MetaRNN

Benign

0.0033

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.16

N;N

REVEL

Benign

0.051

Sift

Benign

0.24

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.0010

B;.

Vest4

0.028

MPC

0.12

ClinPred

0.0086

GERP RS

-4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.058

gMVP

0.035

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over