rs2228000

Positions:

• chr3-14158387-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004628.5(XPC):​c.1496C>T​(p.Ala499Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,613,464 control chromosomes in the GnomAD database, including 50,315 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A499T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.22 (4131 hom., cov: 32)
  • Exomes 𝑓: 0.25 (46184 hom.)
• Consequence: XPC NM_004628.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.00600

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)

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: GnomAd4 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	Protein	UniProt
XPC	NM_004628.5	c.1496C>T	p.Ala499Val	missense_variant	9/16	ENST00000285021.12	NP_004619.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPC	ENST00000285021.12	c.1496C>T	p.Ala499Val	missense_variant	9/16	1	NM_004628.5	ENSP00000285021	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 Cov.: 35 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

GnomAD4 genome AF: 0.215 AC: 32687 AN: 151848 Hom.: 4131 Cov.: 32 AF XY: 0.220 AC XY: 16344 AN XY: 74178

Gnomad4 AFR AF: 0.0911

Gnomad4 AMR AF: 0.241

Gnomad4 ASJ AF: 0.222

Gnomad4 EAS AF: 0.364

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.367

Gnomad4 NFE AF: 0.247

Gnomad4 OTH AF: 0.244

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:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	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. -

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	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. -

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	1.1
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

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

LitVar

Other links and lift over

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