3-14145845-G-C

Position:

• chr3-14145845-G-C

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.*96C>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 0.25 in 1,460,900 control chromosomes in the GnomAD database, including 47,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4412 hom., cov: 32)
  • Exomes 𝑓: 0.25 (43427 hom.)
• Consequence: XPC NM_004628.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.21

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 (BayesDel_noAF=-0.84).
• BP6: Variant 3-14145845-G-C is Benign according to our data. Variant chr3-14145845-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 343560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XPC	NM_004628.5	c.*96C>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.*96C>G		3_prime_UTR_variant	16/16	1	NM_004628.5	P1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34451 AN: 151938 Hom.: 4415 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.444

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.398

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.256

GnomAD3 exomes AF: 0.249 AC: 48463 AN: 194356 Hom.: 6255 AF XY: 0.249 AC XY: 26166 AN XY: 105016

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.228

Gnomad ASJ exome AF: 0.213

Gnomad EAS exome AF: 0.388

Gnomad SAS exome AF: 0.210

Gnomad FIN exome AF: 0.347

Gnomad NFE exome AF: 0.246

Gnomad OTH exome AF: 0.257

GnomAD4 exome AF: 0.253 AC: 331265 AN: 1308844 Hom.: 43427 Cov.: 19 AF XY: 0.252 AC XY: 163836 AN XY: 650832

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.227

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.377

Gnomad4 SAS exome AF: 0.207

Gnomad4 FIN exome AF: 0.344

Gnomad4 NFE exome AF: 0.254

Gnomad4 OTH exome AF: 0.247

GnomAD4 genome AF: 0.227 AC: 34462 AN: 152056 Hom.: 4412 Cov.: 32 AF XY: 0.231 AC XY: 17188 AN XY: 74324

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.247

Gnomad4 ASJ AF: 0.223

Gnomad4 EAS AF: 0.397

Gnomad4 SAS AF: 0.213

Gnomad4 FIN AF: 0.364

Gnomad4 NFE AF: 0.252

Gnomad4 OTH AF: 0.257

Alfa AF: 0.141 Hom.: 403

Bravo AF: 0.215

Asia WGS AF: 0.261 AC: 905 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum, group C Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Apr 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Xeroderma pigmentosum Benign:1

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 07, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.1
DANN	Benign	0.44

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: rs2229090; hg19: chr3-14187345; COSMIC: COSV53205418; COSMIC: COSV53205418;