22-46797461-G-T

Variant names:

• chr22-46797461-G-T
• rs759900287
• NM_014346.5:c.478G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014346.5(TBC1D22A):​c.478G>T​(p.Ala160Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,686 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. A160T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TBC1D22A NM_014346.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.846
• Publications: 1 publications found

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]

ACMG classification

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=0.050276846).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D22A	NM_014346.5	c.478G>T	p.Ala160Ser	missense_variant	Exon 4 of 13	ENST00000337137.9	NP_055161.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D22A	ENST00000337137.9	c.478G>T	p.Ala160Ser	missense_variant	Exon 4 of 13	1	NM_014346.5	ENSP00000336724.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249582 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 6.85e-7 AC: 1 AN: 1460686 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726640

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.0000224 AC: 1 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4902

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60272

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	4.7
DANN	Benign	0.83
DEOGEN2	Benign	0.0019	T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.20	T;T;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.050	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	.;L;.
PhyloP100		0.85
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.020	.;N;N
REVEL	Benign	0.018
Sift	Benign	0.78	.;T;T
Sift4G	Benign	0.90	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.062
MutPred		0.18		.;Gain of phosphorylation at A160 (P = 0.0207);.;
MVP		0.48
MPC		0.36
ClinPred		0.034	T
GERP RS		-5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.018
gMVP		0.24
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs759900287; hg19: chr22-47193358;