Genetic Variant TOB2:p.Ala309Thr (chr22-41436421-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_016272.4(TOB2):c.925G>A(p.Ala309Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

TOB2
NM_016272.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.08

Publications

0 publications found

Variant links:

Genes affected

TOB2 (HGNC:11980): (transducer of ERBB2, 2) TOB2 belongs to the TOB (see TOB1; MIM 605523)/BTG1 (MIM 109580) family of antiproliferative proteins, which are involved in the regulation of cell cycle progression.[supplied by OMIM, Apr 2004]

TOB2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0064424872).

BP6

Variant 22-41436421-C-T is Benign according to our data. Variant chr22-41436421-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3180947.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOB2	NM_016272.4 link	c.925G>A	p.Ala309Thr	missense_variant	Exon 2 of 2	ENST00000327492.4	NP_057356.1	Q14106-1
TOB2	XM_005261315.3 link	c.925G>A	p.Ala309Thr	missense_variant	Exon 2 of 2		XP_005261372.1	Q14106-1
TOB2	XM_006724105.4 link	c.925G>A	p.Ala309Thr	missense_variant	Exon 2 of 2		XP_006724168.1	Q14106-1
TOB2	XM_017028539.2 link	c.925G>A	p.Ala309Thr	missense_variant	Exon 2 of 2		XP_016884028.1	Q14106-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOB2	ENST00000327492.4 link	c.925G>A	p.Ala309Thr	missense_variant	Exon 2 of 2	1	NM_016272.4	ENSP00000331305.3		Q14106-1
TOB2	ENST00000434408.2 link	c.925G>A	p.Ala309Thr	missense_variant	Exon 2 of 2	2		ENSP00000388549.2		B0QXZ4

Frequencies

GnomAD3 genomes

AF:

0.000282

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000111

AC:

AN:

251278

AF XY:

0.0000810

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

33480

American (AMR)

AF:

0.000112

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111994

Other (OTH)

AF:

0.000116

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000282

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000158

Hom.:

Bravo

AF:

0.000382

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000165

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 26, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.019

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.099

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.66

M_CAP

Benign

0.0018

MetaRNN

Benign

0.0064

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.32

PhyloP100

-1.1

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.12

REVEL

Benign

0.069

Sift

Benign

0.54

Sift4G

Benign

0.70

Polyphen

0.0

Vest4

0.050

MVP

0.23

MPC

0.31

ClinPred

0.0054

GERP RS

-12

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.048

gMVP

0.30

Mutation Taster

=90/10

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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