chr3-14145257-C-G

Position:

• chr3-14145257-C-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.*684G>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 0.886 in 686,448 control chromosomes in the GnomAD database, including 270,012 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (59278 hom., cov: 33)
  • Exomes 𝑓: 0.89 (210734 hom.)
• Consequence: XPC NM_004628.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0480

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=-0.89).
• BP6: Variant 3-14145257-C-G is Benign according to our data. Variant chr3-14145257-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 343550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XPC	NM_004628.5	c.*684G>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.*684G>C		3_prime_UTR_variant	16/16	1	NM_004628.5	P1
XPC-AS1	ENST00000420253.3	n.460-65C>G		intron_variant, non_coding_transcript_variant		4
XPC-AS1	ENST00000428681.3	n.374-65C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.882 AC: 134115 AN: 152134 Hom.: 59223 Cov.: 33

Gnomad AFR AF: 0.872

Gnomad AMI AF: 0.921

Gnomad AMR AF: 0.924

Gnomad ASJ AF: 0.883

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.928

Gnomad FIN AF: 0.909

Gnomad MID AF: 0.873

Gnomad NFE AF: 0.861

Gnomad OTH AF: 0.888

GnomAD3 exomes AF: 0.904 AC: 109766 AN: 121382 Hom.: 49803 AF XY: 0.902 AC XY: 59493 AN XY: 65926

Gnomad AFR exome AF: 0.876

Gnomad AMR exome AF: 0.940

Gnomad ASJ exome AF: 0.877

Gnomad EAS exome AF: 0.999

Gnomad SAS exome AF: 0.920

Gnomad FIN exome AF: 0.910

Gnomad NFE exome AF: 0.866

Gnomad OTH exome AF: 0.890

GnomAD4 exome AF: 0.887 AC: 473977 AN: 534196 Hom.: 210734 Cov.: 0 AF XY: 0.888 AC XY: 256281 AN XY: 288562

Gnomad4 AFR exome AF: 0.871

Gnomad4 AMR exome AF: 0.936

Gnomad4 ASJ exome AF: 0.879

Gnomad4 EAS exome AF: 0.991

Gnomad4 SAS exome AF: 0.923

Gnomad4 FIN exome AF: 0.907

Gnomad4 NFE exome AF: 0.864

Gnomad4 OTH exome AF: 0.886

GnomAD4 genome AF: 0.882 AC: 134230 AN: 152252 Hom.: 59278 Cov.: 33 AF XY: 0.886 AC XY: 65973 AN XY: 74436

Gnomad4 AFR AF: 0.872

Gnomad4 AMR AF: 0.924

Gnomad4 ASJ AF: 0.883

Gnomad4 EAS AF: 0.997

Gnomad4 SAS AF: 0.929

Gnomad4 FIN AF: 0.909

Gnomad4 NFE AF: 0.861

Gnomad4 OTH AF: 0.889

Alfa AF: 0.859 Hom.: 6169

Bravo AF: 0.885

Asia WGS AF: 0.958 AC: 3331 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Xeroderma pigmentosum, group C Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.0
DANN	Benign	0.56

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: rs1126547; hg19: chr3-14186757;