8-15540241-C-T

Position:

• chr8-15540241-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The ENST00000382020(TUSC3):​c.-190C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 809,352 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (2 hom.)
• Consequence: TUSC3 ENST00000382020 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15

Genes affected

TUSC3 (HGNC:30242): (tumor suppressor candidate 3) This gene encodes a protein that has been associated with several biological functions including cellular magnesium uptake, protein glycosylation and embryonic development. This protein localizes to the endoplasmic reticulum and acts as a component of the oligosaccharyl transferase complex which is responsible for N-linked protein glycosylation. This gene is a candidate tumor suppressor gene. Homozygous mutations in this gene are associated with autosomal recessive nonsyndromic mental retardation-7 and in the proliferation and invasiveness of several cancers including metastatic pancreatic cancer, ovarian cancer and glioblastoma multiform. [provided by RefSeq, Oct 2017]

TUSC3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00174 (265/152300) while in subpopulation NFE AF= 0.00312 (212/68028). AF 95% confidence interval is 0.00277. There are 0 homozygotes in gnomad4. There are 108 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
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUSC3	NM_006765.4	c.-190C>T		upstream_gene_variant		ENST00000503731.6	NP_006756.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUSC3	ENST00000503731.6	c.-190C>T		upstream_gene_variant		1	NM_006765.4	ENSP00000424544.1

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 265 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00312

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00277 AC: 1817 AN: 657052 Hom.: 2 Cov.: 9 AF XY: 0.00270 AC XY: 882 AN XY: 326242

Gnomad4 AFR exome AF: 0.000595

Gnomad4 AMR exome AF: 0.00113

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000744

Gnomad4 NFE exome AF: 0.00339

Gnomad4 OTH exome AF: 0.00160

GnomAD4 genome AF: 0.00174 AC: 265 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74456

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00312

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00222 Hom.: 0

Bravo AF: 0.00206

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital disorder of glycosylation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Benign	0.97

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs573872013; hg19: chr8-15397750;