3-14145330-A-T

Variant names:

• chr3-14145330-A-T
• rs2470352
• ENST00000608606.1:n.244A>T

Variant summary

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

The ENST00000608606.1(ENSG00000268279):​n.244A>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 0.173 in 697,562 control chromosomes in the GnomAD database, including 12,046 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2412 hom., cov: 32)
  • Exomes 𝑓: 0.17 (9634 hom.)
• Consequence: ENSG00000268279 ENST00000608606.1 non_coding_transcript_exon
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.63
• Publications: 15 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 3-14145330-A-T is Benign according to our data. Variant chr3-14145330-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 343552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPC	NM_004628.5	c.*611T>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.244A>T		non_coding_transcript_exon_variant	Exon 4 of 5	5		ENSP00000476275.1
XPC	ENST00000285021.12	c.*611T>A		3_prime_UTR_variant	Exon 16 of 16	1	NM_004628.5	ENSP00000285021.8

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25257 AN: 151652 Hom.: 2412 Cov.: 32

Gnomad AFR AF: 0.0969

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0951

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.192

GnomAD2 exomes AF: 0.151 AC: 19384 AN: 128366 AF XY: 0.151

Gnomad AFR exome AF: 0.0907

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.000290

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.211

Gnomad OTH exome AF: 0.180

GnomAD4 exome AF: 0.175 AC: 95373 AN: 545792 Hom.: 9634 Cov.: 0 AF XY: 0.173 AC XY: 50986 AN XY: 295454

African (AFR) AF: 0.0963 AC: 1501 AN: 15594

American (AMR) AF: 0.120 AC: 4114 AN: 34206

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 4016 AN: 19972

East Asian (EAS) AF: 0.000249 AC: 8 AN: 32094

South Asian (SAS) AF: 0.104 AC: 6431 AN: 62004

European-Finnish (FIN) AF: 0.233 AC: 7742 AN: 33176

Middle Eastern (MID) AF: 0.158 AC: 384 AN: 2436

European-Non Finnish (NFE) AF: 0.208 AC: 65784 AN: 315974

Other (OTH) AF: 0.178 AC: 5393 AN: 30336

GnomAD4 genome AF: 0.166 AC: 25257 AN: 151770 Hom.: 2412 Cov.: 32 AF XY: 0.164 AC XY: 12195 AN XY: 74146

African (AFR) AF: 0.0967 AC: 4001 AN: 41372

American (AMR) AF: 0.156 AC: 2381 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 723 AN: 3470

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5162

South Asian (SAS) AF: 0.0956 AC: 461 AN: 4822

European-Finnish (FIN) AF: 0.239 AC: 2503 AN: 10488

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.212 AC: 14419 AN: 67908

Other (OTH) AF: 0.190 AC: 398 AN: 2100

Alfa AF: 0.125 Hom.: 306

Bravo AF: 0.158

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely 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

- -

Xeroderma pigmentosum, group C Benign:1

Jan 12, 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	4.1
DANN	Benign	0.69
PhyloP100		1.6
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: rs2470352; hg19: chr3-14186830;