dbSNP rs11545035: TUSC3:p.Ile65Val (chr8-15623134-A-G) – ACMG Classification: Benign (-20 pts)

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. 15/22 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

Publications

16 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: Labcorp Genetics (formerly Invitae), G2P
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 (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 Benign/Likely_benign. ClinVar VariationId 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 passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

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.193A>G	p.Ile65Val	missense	Exon 2 of 11	NP_006756.2
TUSC3	NM_001413679.1		c.193A>G	p.Ile65Val	missense	Exon 2 of 9	NP_001400608.1
TUSC3	NM_001413684.1		c.193A>G	p.Ile65Val	missense	Exon 2 of 10	NP_001400613.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TUSC3	ENST00000503731.6	TSL:1 MANE Select	c.193A>G	p.Ile65Val	missense	Exon 2 of 11	ENSP00000424544.1	Q13454-1
TUSC3	ENST00000382020.8	TSL:1	c.193A>G	p.Ile65Val	missense	Exon 2 of 10	ENSP00000371450.4	Q13454-2
TUSC3	ENST00000947282.1		c.268A>G	p.Ile90Val	missense	Exon 3 of 12	ENSP00000617341.1

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

African (AFR)

AF:

0.00125

AC:

AN:

33472

American (AMR)

AF:

0.00461

AC:

206

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.0307

AC:

803

AN:

26128

East Asian (EAS)

AF:

0.000101

AC:

AN:

39680

South Asian (SAS)

AF:

0.000719

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.00642

AC:

343

AN:

53400

Middle Eastern (MID)

AF:

0.00416

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00768

AC:

8537

AN:

1111884

Other (OTH)

AF:

0.00727

AC:

439

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

547

1094

1641

2188

2735

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

African (AFR)

AF:

0.00154

AC:

AN:

41572

American (AMR)

AF:

0.00425

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0291

AC:

101

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00687

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00805

AC:

548

AN:

68034

Other (OTH)

AF:

0.00992

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

143

190

238

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Intellectual disability, autosomal recessive 7 (2)

not specified (2)

Congenital disorder of glycosylation (1)

Inborn genetic diseases (1)

TUSC3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.078

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.79

M_CAP

Benign

0.0027

MetaRNN

Benign

0.0040

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.5

PhyloP100

6.3

PrimateAI

Benign

0.36

PROVEAN

Benign

0.34

REVEL

Benign

0.15

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.11

MVP

0.18

MPC

0.22

ClinPred

0.019

GERP RS

0.17

PromoterAI

0.020

Neutral

(source)

Varity_R

0.12

gMVP

0.41

Mutation Taster

=100/0

polymorphism

(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

Computational scores

Splicing

Publications

Other links and lift over