8-15650691-T-C

Position:

chr8-15650691-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006765.4(TUSC3):c.309-6T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 1,612,634 control chromosomes in the GnomAD database, including 101,365 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 8064 hom., cov: 32)

Exomes 𝑓: 0.35 ( 93301 hom. )

Consequence

TUSC3
NM_006765.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00004587

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.251

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 8-15650691-T-C is Benign according to our data. Variant chr8-15650691-T-C is described in ClinVar as [Benign]. Clinvar id is 95430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15650691-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUSC3	NM_006765.4 linkuse as main transcript	c.309-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000503731.6	NP_006756.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUSC3	ENST00000503731.6 linkuse as main transcript	c.309-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006765.4	ENSP00000424544	A1	Q13454-1

Frequencies

GnomAD3 genomes

AF:

0.311

AC:

47330

AN:

151980

Hom.:

8052

Cov.:

show subpopulations

Gnomad AFR

AF:

0.177

Gnomad AMI

AF:

0.337

Gnomad AMR

AF:

0.334

Gnomad ASJ

AF:

0.332

Gnomad EAS

AF:

0.417

Gnomad SAS

AF:

0.236

Gnomad FIN

AF:

0.440

Gnomad MID

AF:

0.310

Gnomad NFE

AF:

0.365

Gnomad OTH

AF:

0.305

GnomAD3 exomes

AF:

0.345

AC:

86643

AN:

251342

Hom.:

15628

AF XY:

0.341

AC XY:

46373

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.175

Gnomad AMR exome

AF:

0.374

Gnomad ASJ exome

AF:

0.334

Gnomad EAS exome

AF:

0.428

Gnomad SAS exome

AF:

0.236

Gnomad FIN exome

AF:

0.439

Gnomad NFE exome

AF:

0.359

Gnomad OTH exome

AF:

0.351

GnomAD4 exome

AF:

0.354

AC:

517033

AN:

1460534

Hom.:

93301

Cov.:

AF XY:

0.351

AC XY:

255077

AN XY:

726678

show subpopulations

Gnomad4 AFR exome

AF:

0.170

Gnomad4 AMR exome

AF:

0.372

Gnomad4 ASJ exome

AF:

0.334

Gnomad4 EAS exome

AF:

0.387

Gnomad4 SAS exome

AF:

0.237

Gnomad4 FIN exome

AF:

0.435

Gnomad4 NFE exome

AF:

0.364

Gnomad4 OTH exome

AF:

0.353

GnomAD4 genome

AF:

0.311

AC:

47365

AN:

152100

Hom.:

8064

Cov.:

AF XY:

0.314

AC XY:

23355

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.177

Gnomad4 AMR

AF:

0.335

Gnomad4 ASJ

AF:

0.332

Gnomad4 EAS

AF:

0.418

Gnomad4 SAS

AF:

0.234

Gnomad4 FIN

AF:

0.440

Gnomad4 NFE

AF:

0.365

Gnomad4 OTH

AF:

0.311

Alfa

AF:

0.344

Hom.:

13716

Bravo

AF:

0.302

Asia WGS

AF:

0.340

AC:

1180

AN:

3478

EpiCase

AF:

0.351

EpiControl

AF:

0.353

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 26, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Intellectual disability, autosomal recessive 7

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Congenital disorder of glycosylation

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

-0.77

CADD

Benign

1.4

DANN

Benign

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000046

dbscSNV1_RF

Benign

0.010

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over