Genetic Variant NM_014346.5:c.400C>A (chr22-46793781-C-A) – 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>A(p.Pro134Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000287 in 1,601,678 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 Uncertain significance (★). 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 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

TBC1D22A
NM_014346.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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:

Genome browser will be placed here

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=0.04215759).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D22A	NM_014346.5 link	c.400C>A	p.Pro134Thr	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>A	p.Pro134Thr	missense_variant	Exon 3 of 13	1	NM_014346.5	ENSP00000336724.4		Q8WUA7-1

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000870

AC:

AN:

218272

AF XY:

0.0000832

show subpopulations

Gnomad AFR exome

AF:

0.000159

Gnomad AMR exome

AF:

0.0000623

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000363

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000530

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000248

AC:

AN:

1449610

Hom.:

Cov.:

AF XY:

0.0000375

AC XY:

AN XY:

720382

show subpopulations

African (AFR)

AF:

0.0000602

AC:

AN:

33224

American (AMR)

AF:

0.0000233

AC:

AN:

42870

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25802

East Asian (EAS)

AF:

0.000179

AC:

AN:

39100

South Asian (SAS)

AF:

0.000118

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:

0.0000126

AC:

AN:

1106840

Other (OTH)

AF:

0.0000334

AC:

AN:

59856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000658

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41412

American (AMR)

AF:

0.0000655

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:

0.000207

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:

0.0000441

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000583

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 02, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.400C>A (p.P134T) alteration is located in exon 3 (coding exon 3) of the TBC1D22A gene. This alteration results from a C to A substitution at nucleotide position 400, causing the proline (P) at amino acid position 134 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.69

CADD

Benign

2.7

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.020

T;T;T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.78

T;T;T;T;T

M_CAP

Benign

0.0087

MetaRNN

Benign

0.042

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

.;L;.;.;.

PhyloP100

-0.35

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.1

.;N;N;N;N

REVEL

Benign

0.013

Sift

Benign

0.67

.;T;T;T;T

Sift4G

Benign

0.43

T;T;T;T;T

Polyphen

0.0010, 0.0020

.;B;B;B;.

Vest4

0.091

MutPred

0.14

.;Gain of phosphorylation at P134 (P = 0.0103);Gain of phosphorylation at P134 (P = 0.0103);.;.;

MVP

0.17

MPC

0.43

ClinPred

0.0078

GERP RS

-0.47

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.031

gMVP

0.23

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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.

NM_014346.5:c.400C>A

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