NM_006765.4:c.309-6T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006765.4(TUSC3):c.309-6T>C variant causes a splice region, 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, intron

Scores

Splicing: ADA: 0.00004587

Clinical Significance

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

Conservation

PhyloP100: 0.251

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

intellectual disability
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
intellectual disability, autosomal recessive 7
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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 (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 VariationId is 95430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
TUSC3	NM_006765.4 link	c.309-6T>C		splice_region_variant, intron_variant	Intron 2 of 10	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.309-6T>C		splice_region_variant, intron_variant	Intron 2 of 10	1	NM_006765.4	ENSP00000424544.1		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

GnomAD2 exomes

AF:

0.345

AC:

86643

AN:

251342

AF XY:

0.341

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 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

African (AFR)

AF:

0.170

AC:

5681

AN:

33458

American (AMR)

AF:

0.372

AC:

16639

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.334

AC:

8727

AN:

26122

East Asian (EAS)

AF:

0.387

AC:

15345

AN:

39670

South Asian (SAS)

AF:

0.237

AC:

20458

AN:

86218

European-Finnish (FIN)

AF:

0.435

AC:

23218

AN:

53346

Middle Eastern (MID)

AF:

0.309

AC:

1780

AN:

5764

European-Non Finnish (NFE)

AF:

0.364

AC:

403888

AN:

1110878

Other (OTH)

AF:

0.353

AC:

21297

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

17098

34196

51295

68393

85491

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12666

25332

37998

50664

63330

<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:

0.311

AC:

47365

AN:

152100

Hom.:

8064

Cov.:

AF XY:

0.314

AC XY:

23355

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.177

AC:

7338

AN:

41524

American (AMR)

AF:

0.335

AC:

5113

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.332

AC:

1150

AN:

3466

East Asian (EAS)

AF:

0.418

AC:

2159

AN:

5170

South Asian (SAS)

AF:

0.234

AC:

1128

AN:

4816

European-Finnish (FIN)

AF:

0.440

AC:

4647

AN:

10556

Middle Eastern (MID)

AF:

0.300

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.365

AC:

24781

AN:

67978

Other (OTH)

AF:

0.311

AC:

656

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1570

3140

4710

6280

7850

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

478

956

1434

1912

2390

<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:

0.343

Hom.:

17192

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

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 26, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Sep 04, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Intellectual disability, autosomal recessive 7

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital disorder of glycosylation

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: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 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

(source)

DANN

Benign

0.74

PhyloP100

0.25

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over