rs17121892

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_006765.4(TUSC3):c.912G>A(p.Ser304=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00479 in 1,613,862 control chromosomes in the GnomAD database, including 289 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 135 hom., cov: 33)

Exomes 𝑓: 0.0027 ( 154 hom. )

Consequence

TUSC3
NM_006765.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.85

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.3).

BP6

Variant 8-15743587-G-A is Benign according to our data. Variant chr8-15743587-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.85 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0826 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUSC3	NM_006765.4 linkuse as main transcript	c.912G>A	p.Ser304=	synonymous_variant	8/11	ENST00000503731.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUSC3	ENST00000503731.6 linkuse as main transcript	c.912G>A	p.Ser304=	synonymous_variant	8/11	1	NM_006765.4	A1	Q13454-1

Frequencies

GnomAD3 genomes

AF:

0.0250

AC:

3802

AN:

152094

Hom.:

135

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0851

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0127

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.0215

GnomAD3 exomes

AF:

0.00654

AC:

1641

AN:

250982

Hom.:

AF XY:

0.00486

AC XY:

659

AN XY:

135610

show subpopulations

Gnomad AFR exome

AF:

0.0824

Gnomad AMR exome

AF:

0.00599

Gnomad ASJ exome

AF:

0.00249

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000274

Gnomad OTH exome

AF:

0.00522

GnomAD4 exome

AF:

0.00268

AC:

3922

AN:

1461652

Hom.:

154

Cov.:

AF XY:

0.00223

AC XY:

1622

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.0897

Gnomad4 AMR exome

AF:

0.00675

Gnomad4 ASJ exome

AF:

0.00222

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000138

Gnomad4 OTH exome

AF:

0.00621

GnomAD4 genome

AF:

0.0250

AC:

3806

AN:

152210

Hom.:

135

Cov.:

AF XY:

0.0248

AC XY:

1847

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0850

Gnomad4 AMR

AF:

0.0126

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.0213

Alfa

AF:

0.00553

Hom.:

Bravo

AF:

0.0285

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 26, 2012	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Intellectual disability, autosomal recessive 7

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

- -

TUSC3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Congenital disorder of glycosylation

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

-0.30

CADD

Benign

DANN

Benign

0.72

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

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