rs2228000

chr3-14158387-G-A

• Frequency:
  • Genomes: 𝑓 0.22 (4135 hom., cov: 32)
  • Exomes 𝑓: 0.24 (7936 hom.)
• Consequence: XPC NM_004628 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.00600

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002342701).
• BP6: Variant 3:14158387-G>A is Benign according to our data. Variant chr3-14158387-G-A is described in ClinVar as [Benign]. Clinvar id is 135485. Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XPC	NM_004628.5	c.1496C>T	p.Ala499Val	missense_variant	9/16	ENST00000285021.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XPC	ENST00000285021.12	c.1496C>T	p.Ala499Val	missense_variant	9/16	1	NM_004628.5	P1
XPC-AS1	ENST00000627116.2	n.457-7489G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32678 AN: 151730 Hom.: 4135 Cov.: 32

Gnomad AFR AF: 0.0912

Gnomad AMI AF: 0.444

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.245

GnomAD3 exomes AF: 0.244 AC: 60666 AN: 249122 Hom.: 7936 AF XY: 0.243 AC XY: 32906 AN XY: 135152

Gnomad AFR exome AF: 0.0899

Gnomad AMR exome AF: 0.223

Gnomad ASJ exome AF: 0.212

Gnomad EAS exome AF: 0.361

Gnomad SAS exome AF: 0.198

Gnomad FIN exome AF: 0.356

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.251

GnomAD4 exome AF: 0.247 AC: 360862 AN: 1461616 Hom.: 46184 AF XY: 0.246 AC XY: 178638 AN XY: 727082

Gnomad4 AFR exome AF: 0.0806

Gnomad4 AMR exome AF: 0.225

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.345

Gnomad4 SAS exome AF: 0.198

Gnomad4 FIN exome AF: 0.349

Gnomad4 NFE exome AF: 0.250

Gnomad4 OTH exome AF: 0.239

Alfa AF: 0.242 Hom.: 9175

Bravo AF: 0.202

TwinsUK AF: 0.248 AC: 918

ALSPAC AF: 0.250 AC: 965

ESP6500AA AF: 0.0918 AC: 288

ESP6500EA AF: 0.248 AC: 1778

ExAC AF: 0.237 AC: 28666

Asia WGS AF: 0.236 AC: 820 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK:

Submissions by phenotype

not specified Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, PreventionGenetics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 27, 2018	Variant summary: XPC c.1496C>T (p.Ala499Val) 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 0.24 in 276928 control chromosomes in the gnomAD database, including 8807 homozygotes. The observed variant frequency is approximately 171-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in XPC causing Xeroderma Pigmentosum phenotype (0.0014), strongly suggesting that the variant is benign. The variant has been indicated to be associated with an increased risk of cancer (He_2013). A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
not provided, no assertion provided	reference population	ITMI	Sep 19, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2019	This variant is associated with the following publications: (PMID: 26001739, 23436679, 27153395, 15700316, 20369554, 20193233, 24728327, 23400628, 17575242, 21113018, 19706757, 17882560) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 04, 2022	- -

Xeroderma pigmentosum, group C Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

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

0.083

BayesDel_addAF

Benign

-0.67

T

BayesDel_noAF

Benign

-0.59

Cadd

Benign

0.37

Dann

Benign

0.86

DEOGEN2

Benign

0.094

T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.32

N

LIST_S2

Benign

0.44

T

MetaRNN

Benign

0.0023

T

MetaSVM

Benign

-0.92

T

MutationAssessor

Benign

1.1

L

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.26

T

PROVEAN

Benign

-0.96

N

REVEL

Benign

0.012

Sift

Benign

0.33

T

Sift4G

Benign

0.17

T

Polyphen

0.0040

B

Vest4

0.019

MPC

0.12

ClinPred

0.00058

T

GERP RS

-1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.017

gMVP

0.22

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2228000; hg19: chr3-14199887; COSMIC: COSV53203534; COSMIC: COSV53203534;