NM_014832.5:c.3824T>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_014832.5(TBC1D4):c.3824T>C(p.Val1275Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0749 in 1,613,742 control chromosomes in the GnomAD database, including 12,177 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.18 ( 5386 hom., cov: 32)

Exomes 𝑓: 0.064 ( 6791 hom. )

Consequence

TBC1D4
NM_014832.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 4.43

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.917383E-4).

BP6

Variant 13-75286865-A-G is Benign according to our data. Variant chr13-75286865-A-G is described in ClinVar as [Benign]. Clinvar id is 130861.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D4	NM_014832.5 link	c.3824T>C	p.Val1275Ala	missense_variant	Exon 21 of 21	ENST00000377636.8	NP_055647.2	O60343-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TBC1D4	ENST00000377636.8 link	c.3824T>C	p.Val1275Ala	missense_variant	Exon 21 of 21	2	NM_014832.5	ENSP00000366863.3	O60343-1
TBC1D4	ENST00000431480.6 link	c.3800T>C	p.Val1267Ala	missense_variant	Exon 20 of 20	1		ENSP00000395986.2	O60343-3
TBC1D4	ENST00000377625.6 link	c.3635T>C	p.Val1212Ala	missense_variant	Exon 19 of 19	1		ENSP00000366852.2	O60343-2
TBC1D4	ENST00000648194.1 link	c.3092T>C	p.Val1031Ala	missense_variant	Exon 20 of 20			ENSP00000496983.1	A0A3B3IRT3

Frequencies

GnomAD3 genomes

AF:

0.178

AC:

27099

AN:

151958

Hom.:

5365

Cov.:

show subpopulations

Gnomad AFR

AF:

0.492

Gnomad AMI

AF:

0.0901

Gnomad AMR

AF:

0.101

Gnomad ASJ

AF:

0.0672

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0155

Gnomad FIN

AF:

0.0461

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0593

Gnomad OTH

AF:

0.147

GnomAD3 exomes

AF:

0.0749

AC:

18650

AN:

249138

Hom.:

2339

AF XY:

0.0661

AC XY:

8937

AN XY:

135182

show subpopulations

Gnomad AFR exome

AF:

0.504

Gnomad AMR exome

AF:

0.0545

Gnomad ASJ exome

AF:

0.0646

Gnomad EAS exome

AF:

0.000334

Gnomad SAS exome

AF:

0.0145

Gnomad FIN exome

AF:

0.0413

Gnomad NFE exome

AF:

0.0584

Gnomad OTH exome

AF:

0.0636

GnomAD4 exome

AF:

0.0641

AC:

93712

AN:

1461666

Hom.:

6791

Cov.:

AF XY:

0.0611

AC XY:

44436

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.509

Gnomad4 AMR exome

AF:

0.0597

Gnomad4 ASJ exome

AF:

0.0636

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0153

Gnomad4 FIN exome

AF:

0.0435

Gnomad4 NFE exome

AF:

0.0572

Gnomad4 OTH exome

AF:

0.0767

GnomAD4 genome

AF:

0.179

AC:

27163

AN:

152076

Hom.:

5386

Cov.:

AF XY:

0.173

AC XY:

12881

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.492

Gnomad4 AMR

AF:

0.101

Gnomad4 ASJ

AF:

0.0672

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0151

Gnomad4 FIN

AF:

0.0461

Gnomad4 NFE

AF:

0.0593

Gnomad4 OTH

AF:

0.145

Alfa

AF:

0.0761

Hom.:

2809

Bravo

AF:

0.194

TwinsUK

AF:

0.0596

AC:

221

ALSPAC

AF:

0.0550

AC:

212

ESP6500AA

AF:

0.462

AC:

1770

ESP6500EA

AF:

0.0586

AC:

484

ExAC

AF:

0.0830

AC:

10026

Asia WGS

AF:

0.0400

AC:

137

AN:

3478

EpiCase

AF:

0.0592

EpiControl

AF:

0.0603

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.047

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

6.9

DANN

Benign

0.25

DEOGEN2

Benign

0.017

.;.;.;T

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.035

T;T;T;T

MetaRNN

Benign

0.00049

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.90

.;.;.;N

PrimateAI

Benign

0.41

PROVEAN

Benign

0.83

.;N;N;N

REVEL

Benign

0.087

Sift

Benign

1.0

.;T;T;T

Sift4G

Benign

0.90

.;T;T;T

Polyphen

0.0

.;B;B;B

Vest4

0.024, 0.026, 0.0080

MPC

0.40

ClinPred

0.0055

GERP RS

3.9

Varity_R

0.012

gMVP

0.23

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