rs2470352

chr3-14145330-A-Gchr3-14145330-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_004628.5(XPC):c.*611T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 697,694 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0073 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (7 hom.)
• Consequence: XPC NM_004628.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00726 (1102/151796) while in subpopulation AFR AF= 0.0241 (997/41382). AF 95% confidence interval is 0.0229. There are 21 homozygotes in gnomad4. There are 519 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XPC	NM_004628.5	c.*611T>C		3_prime_UTR_variant	16/16	ENST00000285021.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XPC	ENST00000285021.12	c.*611T>C		3_prime_UTR_variant	16/16	1	NM_004628.5	P1

Frequencies

GnomAD3 genomes AF: 0.00723 AC: 1097 AN: 151678 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.00342

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00385

GnomAD3 exomes AF: 0.00175 AC: 224 AN: 128366 Hom.: 2 AF XY: 0.00136 AC XY: 95 AN XY: 70000

Gnomad AFR exome AF: 0.0246

Gnomad AMR exome AF: 0.00210

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000265

Gnomad OTH exome AF: 0.00302

GnomAD4 exome AF: 0.00110 AC: 600 AN: 545898 Hom.: 7 Cov.: 0 AF XY: 0.000819 AC XY: 242 AN XY: 295520

Gnomad4 AFR exome AF: 0.0246

Gnomad4 AMR exome AF: 0.00251

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000322

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000168

Gnomad4 OTH exome AF: 0.00234

GnomAD4 genome AF: 0.00726 AC: 1102 AN: 151796 Hom.: 21 Cov.: 32 AF XY: 0.00700 AC XY: 519 AN XY: 74160

Gnomad4 AFR AF: 0.0241

Gnomad4 AMR AF: 0.00341

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00381

Alfa AF: 0.000508 Hom.: 306

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Xeroderma pigmentosum, group C Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	4.6
Dann	Benign	0.63

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: rs2470352; hg19: chr3-14186830;