dbSNP rs1555327550: TBC1D4:p.Pro3Thr (chr13-75481761-G-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_014832.5(TBC1D4):c.7C>A(p.Pro3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TBC1D4
NM_014832.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.174

Publications

0 publications found

Variant links:

Genes affected

TBC1D4 (HGNC:19165): (TBC1 domain family member 4) This gene is a member of the Tre-2/BUB2/CDC16 domain family. The protein encoded by this gene is a Rab-GTPase-activating protein, and contains two phopshotyrosine-binding domains (PTB1 and PTB2), a calmodulin-binding domain (CBD), a Rab-GTPase domain, and multiple AKT phosphomotifs. This protein is thought to play an important role in glucose homeostasis by regulating the insulin-dependent trafficking of the glucose transporter 4 (GLUT4), important for removing glucose from the bloodstream into skeletal muscle and fat tissues. Reduced expression of this gene results in an increase in GLUT4 levels at the plasma membrane, suggesting that this protein is important in intracellular retention of GLUT4 under basal conditions. When exposed to insulin, this protein is phosphorylated, dissociates from GLUT4 vesicles, resulting in increased GLUT4 at the cell surface, and enhanced glucose transport. Phosphorylation of this protein by AKT is required for proper translocation of GLUT4 to the cell surface. Individuals homozygous for a mutation in this gene are at higher risk for type 2 diabetes and have higher levels of circulating glucose and insulin levels after glucose ingestion. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

TBC1D4 links:

ENSG00000297284 (HGNC:):

ENSG00000297284 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=0.056664914).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014832.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBC1D4	NM_014832.5	MANE Select	c.7C>A	p.Pro3Thr	missense	Exon 1 of 21	NP_055647.2	O60343-1
TBC1D4	NM_001286658.2		c.7C>A	p.Pro3Thr	missense	Exon 1 of 20	NP_001273587.1	O60343-3
TBC1D4	NM_001286659.2		c.7C>A	p.Pro3Thr	missense	Exon 1 of 19	NP_001273588.1	O60343-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBC1D4	ENST00000377636.8	TSL:2 MANE Select	c.7C>A	p.Pro3Thr	missense	Exon 1 of 21	ENSP00000366863.3	O60343-1
TBC1D4	ENST00000431480.6	TSL:1	c.7C>A	p.Pro3Thr	missense	Exon 1 of 20	ENSP00000395986.2	O60343-3
TBC1D4	ENST00000377625.6	TSL:1	c.7C>A	p.Pro3Thr	missense	Exon 1 of 19	ENSP00000366852.2	O60343-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1425574

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

708010

African (AFR)

AF:

0.00

AC:

AN:

30324

American (AMR)

AF:

0.00

AC:

AN:

38404

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24124

East Asian (EAS)

AF:

0.00

AC:

AN:

37958

South Asian (SAS)

AF:

0.00

AC:

AN:

81430

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5298

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099246

Other (OTH)

AF:

0.00

AC:

AN:

58620

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.029

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.69

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.057

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

PhyloP100

0.17

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.11

REVEL

Benign

0.12

Sift

Benign

0.23

Sift4G

Benign

0.65

Polyphen

0.0

Vest4

0.065

MutPred

0.16

Gain of phosphorylation at P3 (P = 0.0257)

MVP

0.41

MPC

0.37

ClinPred

0.090

GERP RS

-1.9

PromoterAI

-0.022

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.063

gMVP

0.41

Mutation Taster

=299/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over