rs2470458

chr3-14145323-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004628.5(XPC):c.*618A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 696,988 control chromosomes in the GnomAD database, including 12,019 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.17 (2414 hom., cov: 32)
  • Exomes 𝑓: 0.17 (9605 hom.)
• Consequence: XPC NM_004628.5 3_prime_UTR
• Scores: Splicing: ADA: 0.0001236
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.911

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-14145323-T-C is Benign according to our data. Variant chr3-14145323-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 343551.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XPC	NM_004628.5	c.*618A>G		3_prime_UTR_variant	16/16	ENST00000285021.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XPC	ENST00000285021.12	c.*618A>G		3_prime_UTR_variant	16/16	1	NM_004628.5	P1

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25259 AN: 151884 Hom.: 2414 Cov.: 32

Gnomad AFR AF: 0.0967

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0955

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.192

GnomAD3 exomes AF: 0.152 AC: 19308 AN: 127384 Hom.: 1809 AF XY: 0.152 AC XY: 10536 AN XY: 69428

Gnomad AFR exome AF: 0.0912

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.000291

Gnomad SAS exome AF: 0.102

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.211

Gnomad OTH exome AF: 0.180

GnomAD4 exome AF: 0.175 AC: 95254 AN: 544986 Hom.: 9605 Cov.: 0 AF XY: 0.173 AC XY: 50912 AN XY: 294966

Gnomad4 AFR exome AF: 0.0961

Gnomad4 AMR exome AF: 0.120

Gnomad4 ASJ exome AF: 0.201

Gnomad4 EAS exome AF: 0.000249

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.233

Gnomad4 NFE exome AF: 0.208

Gnomad4 OTH exome AF: 0.178

GnomAD4 genome AF: 0.166 AC: 25259 AN: 152002 Hom.: 2414 Cov.: 32 AF XY: 0.164 AC XY: 12200 AN XY: 74290

Gnomad4 AFR AF: 0.0965

Gnomad4 AMR AF: 0.156

Gnomad4 ASJ AF: 0.208

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0960

Gnomad4 FIN AF: 0.238

Gnomad4 NFE AF: 0.212

Gnomad4 OTH AF: 0.190

Alfa AF: 0.204 Hom.: 3272

Bravo AF: 0.157

Asia WGS AF: 0.0420 AC: 148 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

Xeroderma pigmentosum Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Xeroderma pigmentosum, group C Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	8.0
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.018
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: rs2470458; hg19: chr3-14186823;