Genetic Variant TBC1D22A:p.Thr113Met (chr22-46793719-C-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_014346.5(TBC1D22A):c.338C>T(p.Thr113Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00798 in 1,610,722 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0070 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0081 ( 78 hom. )

Consequence

TBC1D22A
NM_014346.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.274

Publications

2 publications found

Variant links:

Genes affected

TBC1D22A (HGNC:1309): (TBC1 domain family member 22A) Enables 14-3-3 protein binding activity and protein homodimerization activity. Predicted to be involved in activation of GTPase activity and intracellular protein transport. [provided by Alliance of Genome Resources, Apr 2022]

TBC1D22A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035664141).

BP6

Variant 22-46793719-C-T is Benign according to our data. Variant chr22-46793719-C-T is described in ClinVar as [Benign]. Clinvar id is 777312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D22A	NM_014346.5 link	c.338C>T	p.Thr113Met	missense_variant	Exon 3 of 13	ENST00000337137.9	NP_055161.1	Q8WUA7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D22A	ENST00000337137.9 link	c.338C>T	p.Thr113Met	missense_variant	Exon 3 of 13	1	NM_014346.5	ENSP00000336724.4		Q8WUA7-1

Frequencies

GnomAD3 genomes

AF:

0.00701

AC:

1067

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00292

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00569

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0243

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00850

Gnomad OTH

AF:

0.00767

GnomAD2 exomes

AF:

0.00751

AC:

1801

AN:

239730

AF XY:

0.00760

show subpopulations

Gnomad AFR exome

AF:

0.00229

Gnomad AMR exome

AF:

0.00431

Gnomad ASJ exome

AF:

0.000308

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0254

Gnomad NFE exome

AF:

0.00955

Gnomad OTH exome

AF:

0.00845

GnomAD4 exome

AF:

0.00808

AC:

11788

AN:

1458428

Hom.:

Cov.:

AF XY:

0.00793

AC XY:

5752

AN XY:

725384

show subpopulations

African (AFR)

AF:

0.00269

AC:

AN:

33426

American (AMR)

AF:

0.00467

AC:

208

AN:

44514

Ashkenazi Jewish (ASJ)

AF:

0.000269

AC:

AN:

26022

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39666

South Asian (SAS)

AF:

0.00109

AC:

AN:

86018

European-Finnish (FIN)

AF:

0.0257

AC:

1339

AN:

52112

Middle Eastern (MID)

AF:

0.00169

AC:

AN:

5330

European-Non Finnish (NFE)

AF:

0.00865

AC:

9611

AN:

1111110

Other (OTH)

AF:

0.00711

AC:

428

AN:

60230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

718

1437

2155

2874

3592

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00700

AC:

1066

AN:

152294

Hom.:

Cov.:

AF XY:

0.00751

AC XY:

559

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00291

AC:

121

AN:

41568

American (AMR)

AF:

0.00569

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5166

South Asian (SAS)

AF:

0.000829

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0243

AC:

258

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00850

AC:

578

AN:

68022

Other (OTH)

AF:

0.00759

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

119

178

238

297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00678

Hom.:

Bravo

AF:

0.00544

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.00642

AC:

ExAC

AF:

0.00742

AC:

896

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00671

EpiControl

AF:

0.00767

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 29, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.25

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0075

T;T;T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.78

T;T;T;T;T

MetaRNN

Benign

0.0036

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

.;N;.;.;.

PhyloP100

-0.27

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.56

.;N;N;N;N

REVEL

Benign

0.036

Sift

Benign

0.11

.;T;T;T;T

Sift4G

Benign

0.11

T;T;T;T;T

Polyphen

0.90, 0.74, 0.61

.;P;P;P;.

Vest4

0.15

MVP

0.21

MPC

0.47

ClinPred

0.0065

GERP RS

-8.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.012

gMVP

0.17

Mutation Taster

=99/1

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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22-46793719-C-T

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