3-14152389-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004628.5(XPC):c.2061G>A(p.Arg687=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,611,184 control chromosomes in the GnomAD database, including 56,955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5328 hom., cov: 32)
  • Exomes 𝑓: 0.26 (51627 hom.)
• Consequence: XPC NM_004628.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 2.36

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 3-14152389-C-T is Benign according to our data. Variant chr3-14152389-C-T is described in ClinVar as [Benign]. Clinvar id is 135469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XPC	NM_004628.5	c.2061G>A	p.Arg687=	synonymous_variant	11/16	ENST00000285021.12
XPC-AS1	XR_001740603.2	n.2589C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XPC	ENST00000285021.12	c.2061G>A	p.Arg687=	synonymous_variant	11/16	1	NM_004628.5	P1
XPC-AS1	ENST00000627116.2	n.456+2392C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39500 AN: 151998 Hom.: 5321 Cov.: 32

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.0418

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.259

GnomAD3 exomes AF: 0.253 AC: 62068 AN: 245744 Hom.: 8333 AF XY: 0.251 AC XY: 33423 AN XY: 133266

Gnomad AFR exome AF: 0.305

Gnomad AMR exome AF: 0.312

Gnomad ASJ exome AF: 0.234

Gnomad EAS exome AF: 0.0394

Gnomad SAS exome AF: 0.289

Gnomad FIN exome AF: 0.229

Gnomad NFE exome AF: 0.259

Gnomad OTH exome AF: 0.240

GnomAD4 exome AF: 0.261 AC: 381438 AN: 1459068 Hom.: 51627 Cov.: 33 AF XY: 0.261 AC XY: 189298 AN XY: 725600

Gnomad4 AFR exome AF: 0.309

Gnomad4 AMR exome AF: 0.310

Gnomad4 ASJ exome AF: 0.228

Gnomad4 EAS exome AF: 0.0387

Gnomad4 SAS exome AF: 0.286

Gnomad4 FIN exome AF: 0.228

Gnomad4 NFE exome AF: 0.267

Gnomad4 OTH exome AF: 0.251

GnomAD4 genome AF: 0.260 AC: 39546 AN: 152116 Hom.: 5328 Cov.: 32 AF XY: 0.258 AC XY: 19193 AN XY: 74374

Gnomad4 AFR AF: 0.301

Gnomad4 AMR AF: 0.258

Gnomad4 ASJ AF: 0.228

Gnomad4 EAS AF: 0.0417

Gnomad4 SAS AF: 0.291

Gnomad4 FIN AF: 0.220

Gnomad4 NFE AF: 0.259

Gnomad4 OTH AF: 0.257

Alfa AF: 0.264 Hom.: 3268

Bravo AF: 0.265

Asia WGS AF: 0.210 AC: 728 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	Jun 16, 2021	Variant summary: XPC c.2061G>A results in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.25 in 245744 control chromosomes in the gnomAD database, including 8333 homozygotes. The observed variant frequency is approximately 357 fold of the estimated maximal expected allele frequency for a pathogenic variant in XPC causing Xeroderma Pigmentosum phenotype (0.00071), strongly suggesting that the variant is benign. The variant c.2061G>A, has been reported in the literature (example: PMID: 27285993, 10766188). One ClinVar submitter (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	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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
BayesDel_noAF	Benign	-0.38
Cadd	Benign	12
Dann	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2227998; hg19: chr3-14193889; COSMIC: COSV53204988; COSMIC: COSV53204988;