Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_006765.4(TUSC3):c.912G>A(p.Ser304Ser) 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

Publications

3 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 -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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006765.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TUSC3	NM_006765.4	MANE Select	c.912G>A	p.Ser304Ser	synonymous	Exon 8 of 11	NP_006756.2
TUSC3	NM_001413679.1		c.912G>A	p.Ser304Ser	synonymous	Exon 8 of 9	NP_001400608.1
TUSC3	NM_001413684.1		c.912G>A	p.Ser304Ser	synonymous	Exon 8 of 10	NP_001400613.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TUSC3	ENST00000503731.6	TSL:1 MANE Select	c.912G>A	p.Ser304Ser	synonymous	Exon 8 of 11	ENSP00000424544.1
TUSC3	ENST00000382020.8	TSL:1	c.912G>A	p.Ser304Ser	synonymous	Exon 8 of 10	ENSP00000371450.4
TUSC3	ENST00000506802.5	TSL:5	c.912G>A	p.Ser304Ser	synonymous	Exon 8 of 9	ENSP00000425777.1

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

GnomAD2 exomes

AF:

0.00654

AC:

1641

AN:

250982

AF XY:

0.00486

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 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

African (AFR)

AF:

0.0897

AC:

3004

AN:

33476

American (AMR)

AF:

0.00675

AC:

302

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00222

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39682

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00364

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000138

AC:

153

AN:

1111824

Other (OTH)

AF:

0.00621

AC:

375

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

210

420

630

840

1050

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

200

300

400

500

<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:

0.0250

AC:

3806

AN:

152210

Hom.:

135

Cov.:

AF XY:

0.0248

AC XY:

1847

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0850

AC:

3528

AN:

41528

American (AMR)

AF:

0.0126

AC:

193

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.000415

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

68022

Other (OTH)

AF:

0.0213

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

183

366

550

733

916

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.00854

Hom.:

Bravo

AF:

0.0285

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Congenital disorder of glycosylation (1)

Inborn genetic diseases (1)

Intellectual disability, autosomal recessive 7 (1)

TUSC3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.72

PhyloP100

1.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over