Genetic Variant TBC1D22A:p.Pro134Ala (chr22-46793781-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_014346.5(TBC1D22A):c.400C>G(p.Pro134Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,601,704 control chromosomes in the GnomAD database, including 271 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.012 ( 22 hom., cov: 33)

Exomes 𝑓: 0.015 ( 249 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027392805).

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0149 (21544/1449522) while in subpopulation NFE AF = 0.0159 (17631/1106790). AF 95% confidence interval is 0.0157. There are 249 homozygotes in GnomAdExome4. There are 10464 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D22A	NM_014346.5 link	c.400C>G	p.Pro134Ala	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>G	p.Pro134Ala	missense_variant	Exon 3 of 13	1	NM_014346.5	ENSP00000336724.4		Q8WUA7-1

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1867

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00268

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00367

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00498

Gnomad FIN

AF:

0.0532

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0156

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.0120

AC:

2621

AN:

218272

AF XY:

0.0117

show subpopulations

Gnomad AFR exome

AF:

0.00223

Gnomad AMR exome

AF:

0.00227

Gnomad ASJ exome

AF:

0.00698

Gnomad EAS exome

AF:

0.000121

Gnomad FIN exome

AF:

0.0502

Gnomad NFE exome

AF:

0.0136

Gnomad OTH exome

AF:

0.00981

GnomAD4 exome

AF:

0.0149

AC:

21544

AN:

1449522

Hom.:

249

Cov.:

AF XY:

0.0145

AC XY:

10464

AN XY:

720332

show subpopulations

African (AFR)

AF:

0.00205

AC:

AN:

33224

American (AMR)

AF:

0.00245

AC:

105

AN:

42868

Ashkenazi Jewish (ASJ)

AF:

0.00709

AC:

183

AN:

25800

East Asian (EAS)

AF:

0.0000512

AC:

AN:

39100

South Asian (SAS)

AF:

0.00571

AC:

485

AN:

84974

European-Finnish (FIN)

AF:

0.0474

AC:

2427

AN:

51216

Middle Eastern (MID)

AF:

0.00404

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.0159

AC:

17631

AN:

1106790

Other (OTH)

AF:

0.0104

AC:

620

AN:

59856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

1260

2520

3780

5040

6300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0123

AC:

1867

AN:

152182

Hom.:

Cov.:

AF XY:

0.0138

AC XY:

1028

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.00267

AC:

111

AN:

41534

American (AMR)

AF:

0.00366

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00498

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0532

AC:

565

AN:

10612

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0156

AC:

1062

AN:

67982

Other (OTH)

AF:

0.00568

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

100

200

300

400

500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0123

Hom.:

Bravo

AF:

0.00834

TwinsUK

AF:

0.0181

AC:

ALSPAC

AF:

0.0130

AC:

ESP6500AA

AF:

0.00117

AC:

ESP6500EA

AF:

0.00831

AC:

ExAC

AF:

0.00955

AC:

1146

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.72

CADD

Benign

1.4

(source)

DANN

Benign

0.25

DEOGEN2

Benign

0.021

T;T;T;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.74

T;T;T;T;T

MetaRNN

Benign

0.0027

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.86

.;L;.;.;.

PhyloP100

-0.35

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.94

.;N;N;N;N

REVEL

Benign

0.015

Sift

Benign

0.83

.;T;T;T;T

Sift4G

Benign

0.62

T;T;T;T;T

Polyphen

0.0

.;B;B;B;.

Vest4

0.082

MPC

0.38

ClinPred

0.0012

GERP RS

-0.47

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.019

gMVP

0.17

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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-G

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