3-14145845-G-C

Variant names:

• chr3-14145845-G-C
• rs2229090
• ENST00000476581.6:n.*2372C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000476581.6(XPC):​n.*2372C>G variant causes a non coding transcript exon 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 ENST00000476581.6 non_coding_transcript_exon
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.21
• Publications: 35 publications found

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]

ENSG00000268279 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
XPC	NM_004628.5	c.*96C>G		3_prime_UTR_variant	Exon 16 of 16	ENST00000285021.12	NP_004619.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPC	ENST00000285021.12	c.*96C>G		3_prime_UTR_variant	Exon 16 of 16	1	NM_004628.5	ENSP00000285021.8
ENSG00000268279	ENST00000608606.1	n.*198+162G>C		intron_variant	Intron 4 of 4	5		ENSP00000476275.1

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

GnomAD2 exomes AF: 0.249 AC: 48463 AN: 194356 AF XY: 0.249

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 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

African (AFR) AF: 0.108 AC: 3224 AN: 29760

American (AMR) AF: 0.227 AC: 8609 AN: 37856

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 4965 AN: 22818

East Asian (EAS) AF: 0.377 AC: 14395 AN: 38222

South Asian (SAS) AF: 0.207 AC: 16047 AN: 77480

European-Finnish (FIN) AF: 0.344 AC: 16394 AN: 47616

Middle Eastern (MID) AF: 0.195 AC: 744 AN: 3810

European-Non Finnish (NFE) AF: 0.254 AC: 253385 AN: 996716

Other (OTH) AF: 0.247 AC: 13502 AN: 54566

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

African (AFR) AF: 0.117 AC: 4866 AN: 41506

American (AMR) AF: 0.247 AC: 3780 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 773 AN: 3470

East Asian (EAS) AF: 0.397 AC: 2039 AN: 5130

South Asian (SAS) AF: 0.213 AC: 1026 AN: 4816

European-Finnish (FIN) AF: 0.364 AC: 3848 AN: 10584

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.252 AC: 17130 AN: 67936

Other (OTH) AF: 0.257 AC: 542 AN: 2112

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum, group C Benign:3

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 26, 2017

Counsyl

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 07, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Xeroderma pigmentosum Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.1
DANN	Benign	0.44
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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