NM_006765.4:c.38C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_006765.4(TUSC3):c.38C>T(p.Ala13Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000676 in 1,605,990 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00069 ( 2 hom. )

Consequence

TUSC3
NM_006765.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6B:1

Conservation

PhyloP100: 1.42

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020807922).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000545 (83/152228) while in subpopulation NFE AF= 0.000882 (60/68036). AF 95% confidence interval is 0.000703. There are 0 homozygotes in gnomad4. There are 43 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 rank	MANE	Protein	UniProt
TUSC3	NM_006765.4 link	c.38C>T	p.Ala13Val	missense_variant	Exon 1 of 11	ENST00000503731.6	NP_006756.2	Q13454-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUSC3	ENST00000503731.6 link	c.38C>T	p.Ala13Val	missense_variant	Exon 1 of 11	1	NM_006765.4	ENSP00000424544.1		Q13454-1

Frequencies

GnomAD3 genomes

AF:

0.000545

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000587

AC:

135

AN:

229794

Hom.:

AF XY:

0.000695

AC XY:

AN XY:

126554

show subpopulations

Gnomad AFR exome

AF:

0.000149

Gnomad AMR exome

AF:

0.000300

Gnomad ASJ exome

AF:

0.00147

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000271

Gnomad FIN exome

AF:

0.000526

Gnomad NFE exome

AF:

0.000890

Gnomad OTH exome

AF:

0.000177

GnomAD4 exome

AF:

0.000690

AC:

1003

AN:

1453762

Hom.:

Cov.:

AF XY:

0.000700

AC XY:

506

AN XY:

723060

show subpopulations

Gnomad4 AFR exome

AF:

0.000122

Gnomad4 AMR exome

AF:

0.000250

Gnomad4 ASJ exome

AF:

0.00112

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000340

Gnomad4 FIN exome

AF:

0.000290

Gnomad4 NFE exome

AF:

0.000781

Gnomad4 OTH exome

AF:

0.000650

GnomAD4 genome

AF:

0.000545

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.000882

Gnomad4 OTH

AF:

0.00143

Alfa

AF:

0.000686

Hom.:

Bravo

AF:

0.000548

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000468

AC:

ExAC

AF:

0.000480

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal recessive 7

Uncertain:2

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 13 of the TUSC3 protein (p.Ala13Val). This variant is present in population databases (rs200808372, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of TUSC3-related conditions (PMID: 28820871). ClinVar contains an entry for this variant (Variation ID: 547986). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jul 05, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:2

Sep 03, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with ADHD and a clinical diagnosis of fetal alcohol syndrome (de la Morena-Barrio et al., 2018); This variant is associated with the following publications: (PMID: Kubo2019[article], 33206719, 28820871) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Inborn genetic diseases

Uncertain:1

Mar 15, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.38C>T (p.A13V) alteration is located in exon 1 (coding exon 1) of the TUSC3 gene. This alteration results from a C to T substitution at nucleotide position 38, causing the alanine (A) at amino acid position 13 to be replaced by a valine (V). The p.A13V alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital disorder of glycosylation

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

TUSC3-related disorder

Benign:1

Mar 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.088

.;T;.;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.25

LIST_S2

Uncertain

0.88

D;D;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.021

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;.;.;L

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.30

N;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.34

T;T;T;T

Sift4G

Benign

0.63

T;T;T;T

Polyphen

0.0030

B;B;B;B

Vest4

0.38

MVP

0.27

MPC

0.26

ClinPred

0.012

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.066

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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