rs2733532

chr3-14146199-T-Cchr3-14146199-T-G

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.2605-40A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.617 in 1,548,762 control chromosomes in the GnomAD database, including 297,297 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (32936 hom., cov: 27)
  • Exomes 𝑓: 0.61 (264361 hom.)
• Consequence: XPC NM_004628.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.605

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=-0.88).
• BP6: Variant 3-14146199-T-C is Benign according to our data. Variant chr3-14146199-T-C is described in ClinVar as [Benign]. Clinvar id is 259471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XPC	NM_004628.5	c.2605-40A>G		intron_variant		ENST00000285021.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XPC	ENST00000285021.12	c.2605-40A>G		intron_variant		1	NM_004628.5	P1

Frequencies

GnomAD3 genomes AF: 0.656 AC: 99151 AN: 151088 Hom.: 32886 Cov.: 27

Gnomad AFR AF: 0.746

Gnomad AMI AF: 0.704

Gnomad AMR AF: 0.676

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.642

Gnomad SAS AF: 0.659

Gnomad FIN AF: 0.702

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.598

Gnomad OTH AF: 0.648

GnomAD3 exomes AF: 0.640 AC: 110034 AN: 172046 Hom.: 35282 AF XY: 0.635 AC XY: 58833 AN XY: 92710

Gnomad AFR exome AF: 0.751

Gnomad AMR exome AF: 0.709

Gnomad ASJ exome AF: 0.530

Gnomad EAS exome AF: 0.648

Gnomad SAS exome AF: 0.648

Gnomad FIN exome AF: 0.695

Gnomad NFE exome AF: 0.600

Gnomad OTH exome AF: 0.600

GnomAD4 exome AF: 0.613 AC: 856984 AN: 1397556 Hom.: 264361 Cov.: 27 AF XY: 0.612 AC XY: 423760 AN XY: 692150

Gnomad4 AFR exome AF: 0.752

Gnomad4 AMR exome AF: 0.705

Gnomad4 ASJ exome AF: 0.529

Gnomad4 EAS exome AF: 0.623

Gnomad4 SAS exome AF: 0.647

Gnomad4 FIN exome AF: 0.692

Gnomad4 NFE exome AF: 0.603

Gnomad4 OTH exome AF: 0.607

GnomAD4 genome AF: 0.657 AC: 99276 AN: 151206 Hom.: 32936 Cov.: 27 AF XY: 0.662 AC XY: 48824 AN XY: 73804

Gnomad4 AFR AF: 0.746

Gnomad4 AMR AF: 0.676

Gnomad4 ASJ AF: 0.533

Gnomad4 EAS AF: 0.642

Gnomad4 SAS AF: 0.660

Gnomad4 FIN AF: 0.702

Gnomad4 NFE AF: 0.598

Gnomad4 OTH AF: 0.651

Alfa AF: 0.614 Hom.: 7227

Bravo AF: 0.659

Asia WGS AF: 0.684 AC: 2376 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Xeroderma pigmentosum group A Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2019

- -

Xeroderma pigmentosum, group C Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	2.9
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2733532; hg19: chr3-14187699; COSMIC: COSV53204549; COSMIC: COSV53204549;