chr3-14152389-C-T

Position:

chr3-14152389-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_004628.5(XPC):c.2061G>A(p.Arg687Arg) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 2.36

Variant links:

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 links:

XPC-AS1 (HGNC:55014): (XPC antisense RNA 1)

XPC-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
XPC	NM_004628.5 link	c.2061G>A	p.Arg687Arg	synonymous_variant	11/16	ENST00000285021.12	NP_004619.3	Q01831-1X5DRB1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPC	ENST00000285021.12 link	c.2061G>A	p.Arg687Arg	synonymous_variant	11/16	1	NM_004628.5	ENSP00000285021.8		Q01831-1

Frequencies

GnomAD3 genomes

AF:

0.260

AC:

39500

AN:

151998

Hom.:

5321

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.261

AC XY:

189298

AN XY:

725600

show subpopulations

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.:

AF XY:

0.258

AC XY:

19193

AN XY:

74374

show subpopulations

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:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	- -

not specified

Benign:2Other: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. -

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over