3-14145317-T-G

Variant names:

• chr3-14145317-T-G
• rs548142411
• NM_004628.5:c.*624A>C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_004628.5(XPC):​c.*624A>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 0.000521 in 697,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: XPC NM_004628.5 3_prime_UTR
• Scores: Splicing: ADA: 0.001800
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.758

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

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00129 (196/152228) while in subpopulation AFR AF= 0.00417 (173/41526). AF 95% confidence interval is 0.00366. There are 0 homozygotes in gnomad4. There are 88 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPC	NM_004628.5	c.*624A>C		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	c.*624A>C		3_prime_UTR_variant	Exon 16 of 16	1	NM_004628.5	ENSP00000285021.8
ENSG00000268279	ENST00000608606.1	n.236-5T>G		splice_region_variant, intron_variant	Intron 3 of 4	5		ENSP00000476275.1

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00418

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000378 AC: 48 AN: 127124 Hom.: 0 AF XY: 0.000260 AC XY: 18 AN XY: 69180

Gnomad AFR exome AF: 0.00364

Gnomad AMR exome AF: 0.000339

Gnomad ASJ exome AF: 0.000251

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000749

Gnomad NFE exome AF: 0.000164

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.000306 AC: 167 AN: 544926 Hom.: 0 Cov.: 0 AF XY: 0.000217 AC XY: 64 AN XY: 294926

Gnomad4 AFR exome AF: 0.00488

Gnomad4 AMR exome AF: 0.000382

Gnomad4 ASJ exome AF: 0.000201

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000693

Gnomad4 NFE exome AF: 0.0000855

Gnomad4 OTH exome AF: 0.000725

GnomAD4 genome AF: 0.00129 AC: 196 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74454

Gnomad4 AFR AF: 0.00417

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000854 Hom.: 0

Bravo AF: 0.00169

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum, group C Uncertain:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jul 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.0
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0018
dbscSNV1_RF	Benign	0.026
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.22		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs548142411; hg19: chr3-14186817;