Genetic Variant TBC1D22A:p.Pro134Ser (chr22-46793781-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014346.5(TBC1D22A):c.400C>T(p.Pro134Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000312 in 1,601,676 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P134R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

TBC1D22A
NM_014346.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.346

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06223762).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D22A	NM_014346.5 link	c.400C>T	p.Pro134Ser	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.400C>T	p.Pro134Ser	missense_variant	Exon 3 of 13	1	NM_014346.5	ENSP00000336724.4		Q8WUA7-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000916

AC:

AN:

218272

AF XY:

0.00000832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000212

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1449608

Hom.:

Cov.:

AF XY:

0.00000416

AC XY:

AN XY:

720380

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33224

American (AMR)

AF:

0.00

AC:

AN:

42870

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25802

East Asian (EAS)

AF:

0.00

AC:

AN:

39098

South Asian (SAS)

AF:

0.00

AC:

AN:

84978

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1106840

Other (OTH)

AF:

0.0000167

AC:

AN:

59856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41412

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.63

CADD

Benign

2.6

(source)

DANN

Benign

0.31

DEOGEN2

Benign

0.011

T;T;T;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.80

T;T;T;T;T

M_CAP

Benign

0.0078

MetaRNN

Benign

0.062

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

.;L;.;.;.

PhyloP100

-0.35

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.72

.;N;N;N;N

REVEL

Benign

0.019

Sift

Benign

1.0

.;T;T;T;T

Sift4G

Benign

0.75

T;T;T;T;T

Polyphen

0.015, 0.0020, 0.0010

.;B;B;B;.

Vest4

0.17

MutPred

0.18

.;Gain of phosphorylation at P134 (P = 0.0043);Gain of phosphorylation at P134 (P = 0.0043);.;.;

MVP

0.28

MPC

0.40

ClinPred

0.018

GERP RS

-0.47

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.023

gMVP

0.22

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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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22-46793781-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over