rs56223054

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_014832.5(TBC1D4):c.1856C>T(p.Pro619Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00453 in 1,614,104 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0034 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 15 hom. )

Consequence

TBC1D4
NM_014832.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.96

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004371673).

BP6

Variant 13-75326374-G-A is Benign according to our data. Variant chr13-75326374-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 436950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-75326374-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D4	NM_014832.5 linkuse as main transcript	c.1856C>T	p.Pro619Leu	missense_variant	10/21	ENST00000377636.8	NP_055647.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBC1D4	ENST00000377636.8 linkuse as main transcript	c.1856C>T	p.Pro619Leu	missense_variant	10/21	2	NM_014832.5	ENSP00000366863	A1	O60343-1

Frequencies

GnomAD3 genomes

AF:

0.00336

AC:

511

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000749

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00478

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00540

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00325

AC:

807

AN:

248676

Hom.:

AF XY:

0.00343

AC XY:

463

AN XY:

134960

show subpopulations

Gnomad AFR exome

AF:

0.000581

Gnomad AMR exome

AF:

0.00290

Gnomad ASJ exome

AF:

0.00447

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00150

Gnomad FIN exome

AF:

0.000649

Gnomad NFE exome

AF:

0.00500

Gnomad OTH exome

AF:

0.00512

GnomAD4 exome

AF:

0.00465

AC:

6804

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00460

AC XY:

3348

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.00306

Gnomad4 ASJ exome

AF:

0.00448

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00130

Gnomad4 FIN exome

AF:

0.000842

Gnomad4 NFE exome

AF:

0.00552

Gnomad4 OTH exome

AF:

0.00369

GnomAD4 genome

AF:

0.00336

AC:

511

AN:

152216

Hom.:

Cov.:

AF XY:

0.00290

AC XY:

216

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.00477

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.00540

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00399

Hom.:

Bravo

AF:

0.00339

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000742

AC:

ESP6500EA

AF:

0.00647

AC:

ExAC

AF:

0.00332

AC:

402

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00463

EpiControl

AF:

0.00522

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 14, 2017

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

TBC1D4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 02, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.016

.;.;.;T;T

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.32

T;T;T;T;T

MetaRNN

Benign

0.0044

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.6

.;N;N;N;.

MutationTaster

Benign

0.51

D;D;N;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

1.3

.;N;N;N;N

REVEL

Benign

0.099

Sift

Benign

0.37

.;T;T;T;T

Sift4G

Benign

0.81

.;T;T;T;.

Polyphen

0.0

.;B;B;B;.

Vest4

0.19, 0.11, 0.13

MVP

0.45

MPC

0.34

ClinPred

0.010

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.043

gMVP

0.13

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