3-14145489-C-T

Variant names:

• chr3-14145489-C-T
• rs554938831
• ENST00000608606.1:n.*4C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000608606.1(ENSG00000268279):​n.*4C>T 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 0.00012 in 697,704 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: ENSG00000268279 ENST00000608606.1 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.04
• Publications: 0 publications found

Genes affected

ENSG00000268279 (HGNC:):

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPC	NM_004628.5	c.*452G>A		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
ENSG00000268279	ENST00000608606.1	n.*4C>T		non_coding_transcript_exon_variant	Exon 4 of 5	5		ENSP00000476275.1
XPC	ENST00000285021.12	c.*452G>A		3_prime_UTR_variant	Exon 16 of 16	1	NM_004628.5	ENSP00000285021.8
ENSG00000268279	ENST00000608606.1	n.*4C>T		3_prime_UTR_variant	Exon 4 of 5	5		ENSP00000476275.1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152054 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000323 AC: 42 AN: 129976 AF XY: 0.000352

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000412

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00336

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000119 AC: 65 AN: 545532 Hom.: 0 Cov.: 0 AF XY: 0.000129 AC XY: 38 AN XY: 295046

African (AFR) AF: 0.00 AC: 0 AN: 15636

American (AMR) AF: 0.0000289 AC: 1 AN: 34614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19976

East Asian (EAS) AF: 0.00112 AC: 36 AN: 32052

South Asian (SAS) AF: 0.000239 AC: 15 AN: 62634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2434

European-Non Finnish (NFE) AF: 0.0000286 AC: 9 AN: 314730

Other (OTH) AF: 0.000132 AC: 4 AN: 30304

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152172 Hom.: 1 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74394

African (AFR) AF: 0.0000241 AC: 1 AN: 41504

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5172

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000102

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Xeroderma pigmentosum, group C Uncertain:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.21
DANN	Benign	0.69
PhyloP100		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs554938831; hg19: chr3-14186989;