8-15623134-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006765.4(TUSC3):c.193A>G(p.Ile65Val) variant causes a missense change. The variant allele was found at a frequency of 0.00703 in 1,613,952 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0058 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0072 ( 51 hom. )

Consequence

TUSC3
NM_006765.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 6.32

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00399366).

BP6

Variant 8-15623134-A-G is Benign according to our data. Variant chr8-15623134-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 130692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00584 (890/152328) while in subpopulation NFE AF = 0.00805 (548/68034). AF 95% confidence interval is 0.0075. There are 5 homozygotes in GnomAd4. There are 407 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUSC3	NM_006765.4 link	c.193A>G	p.Ile65Val	missense_variant	Exon 2 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.193A>G	p.Ile65Val	missense_variant	Exon 2 of 11	1	NM_006765.4	ENSP00000424544.1		Q13454-1

Frequencies

GnomAD3 genomes

AF:

0.00585

AC:

890

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.00425

Gnomad ASJ

AF:

0.0291

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00687

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00807

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00664

AC:

1669

AN:

251258

AF XY:

0.00684

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00452

Gnomad ASJ exome

AF:

0.0313

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00624

Gnomad NFE exome

AF:

0.00857

Gnomad OTH exome

AF:

0.00799

GnomAD4 exome

AF:

0.00716

AC:

10460

AN:

1461624

Hom.:

Cov.:

AF XY:

0.00706

AC XY:

5135

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.00125

AC:

AN:

33472

Gnomad4 AMR exome

AF:

0.00461

AC:

206

AN:

44700

Gnomad4 ASJ exome

AF:

0.0307

AC:

803

AN:

26128

Gnomad4 EAS exome

AF:

0.000101

AC:

AN:

39680

Gnomad4 SAS exome

AF:

0.000719

AC:

AN:

86210

Gnomad4 FIN exome

AF:

0.00642

AC:

343

AN:

53400

Gnomad4 NFE exome

AF:

0.00768

AC:

8537

AN:

1111884

Gnomad4 Remaining exome

AF:

0.00727

AC:

439

AN:

60384

Heterozygous variant carriers

547

1094

1641

2188

2735

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

320

640

960

1280

1600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00584

AC:

890

AN:

152328

Hom.:

Cov.:

AF XY:

0.00546

AC XY:

407

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00154

AC:

0.0015395

AN:

0.0015395

Gnomad4 AMR

AF:

0.00425

AC:

0.00424837

AN:

0.00424837

Gnomad4 ASJ

AF:

0.0291

AC:

0.0290899

AN:

0.0290899

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.000414

AC:

0.00041425

AN:

0.00041425

Gnomad4 FIN

AF:

0.00687

AC:

0.00687382

AN:

0.00687382

Gnomad4 NFE

AF:

0.00805

AC:

0.0080548

AN:

0.0080548

Gnomad4 OTH

AF:

0.00992

AC:

0.00992439

AN:

0.00992439

Heterozygous variant carriers

143

190

238

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00758

Hom.:

Bravo

AF:

0.00597

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00872

AC:

ExAC

AF:

0.00646

AC:

784

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00901

EpiControl

AF:

0.00913

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Mar 31, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TUSC3: BP4, BS2 -

Sep 14, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Jan 11, 2017

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability, autosomal recessive 7

Benign:2

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Aug 18, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

TUSC3-related disorder

Benign:1

Oct 15, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.56

DEOGEN2

Benign

0.078

.;T;.;T;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.79

T;T;T;T;T

M_CAP

Benign

0.0027

MetaRNN

Benign

0.0040

T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.5

N;.;.;N;.

PrimateAI

Benign

0.36

PROVEAN

Benign

0.34

N;N;N;N;.

REVEL

Benign

0.15

Sift

Benign

1.0

T;T;T;T;.

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0

B;B;B;B;.

Vest4

0.11

MVP

0.18

MPC

0.22

ClinPred

0.019

GERP RS

0.17

Varity_R

0.12

gMVP

0.41

Mutation Taster

=100/0

polymorphism

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