13-75286927-T-A

Position:

chr13-75286927-T-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_014832.5(TBC1D4):c.3762A>T(p.Glu1254Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

TBC1D4
NM_014832.5 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.490

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.006940663).

BP6

Variant 13-75286927-T-A is Benign according to our data. Variant chr13-75286927-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 130860.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D4	NM_014832.5 linkuse as main transcript	c.3762A>T	p.Glu1254Asp	missense_variant	21/21	ENST00000377636.8	NP_055647.2	O60343-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TBC1D4	ENST00000377636.8 linkuse as main transcript	c.3762A>T	p.Glu1254Asp	missense_variant	21/21	2	NM_014832.5	ENSP00000366863.3	O60343-1
TBC1D4	ENST00000431480.6 linkuse as main transcript	c.3738A>T	p.Glu1246Asp	missense_variant	20/20	1		ENSP00000395986.2	O60343-3
TBC1D4	ENST00000377625.6 linkuse as main transcript	c.3573A>T	p.Glu1191Asp	missense_variant	19/19	1		ENSP00000366852.2	O60343-2
TBC1D4	ENST00000648194.1 linkuse as main transcript	c.3030A>T	p.Glu1010Asp	missense_variant	20/20			ENSP00000496983.1	A0A3B3IRT3

Frequencies

GnomAD3 genomes

AF:

0.000690

AC:

105

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00239

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

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

GnomAD3 exomes

AF:

0.000205

AC:

AN:

249254

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135264

show subpopulations

Gnomad AFR exome

AF:

0.00304

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000862

AC:

126

AN:

1461758

Hom.:

Cov.:

AF XY:

0.0000715

AC XY:

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.00290

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000696

AC:

106

AN:

152280

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00241

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000119

Hom.:

Bravo

AF:

0.000786

ESP6500AA

AF:

0.00190

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000240

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

.;.;.;T

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.45

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.86

D;D;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.0069

T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.6

.;.;.;L

MutationTaster

Benign

0.98

D;D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.0

.;N;N;N

REVEL

Benign

0.033

Sift

Benign

0.11

.;T;T;T

Sift4G

Benign

0.15

.;T;T;T

Polyphen

0.010, 0.0070, 0.0030

.;B;B;B

Vest4

0.13, 0.10, 0.12

MutPred

0.27

.;.;.;Gain of catalytic residue at M1256 (P = 0.053);

MVP

0.41

MPC

0.31

ClinPred

0.012

GERP RS

0.15

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.054

gMVP

0.39

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over