chr13-75292148-G-A

Position:

chr13-75292148-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014832.5(TBC1D4):c.3440C>T(p.Thr1147Met) variant causes a missense change. The variant allele was found at a frequency of 0.102 in 1,609,120 control chromosomes in the GnomAD database, including 9,775 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.077 ( 629 hom., cov: 32)

Exomes 𝑓: 0.10 ( 9146 hom. )

Consequence

TBC1D4
NM_014832.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.70

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015574992).

BP6

Variant 13-75292148-G-A is Benign according to our data. Variant chr13-75292148-G-A is described in ClinVar as [Benign]. Clinvar id is 130552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D4	NM_014832.5 linkuse as main transcript	c.3440C>T	p.Thr1147Met	missense_variant	19/21	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.3440C>T	p.Thr1147Met	missense_variant	19/21	2	NM_014832.5	ENSP00000366863.3	O60343-1
TBC1D4	ENST00000431480.6 linkuse as main transcript	c.3416C>T	p.Thr1139Met	missense_variant	18/20	1		ENSP00000395986.2	O60343-3
TBC1D4	ENST00000377625.6 linkuse as main transcript	c.3251C>T	p.Thr1084Met	missense_variant	17/19	1		ENSP00000366852.2	O60343-2
TBC1D4	ENST00000648194.1 linkuse as main transcript	c.2708C>T	p.Thr903Met	missense_variant	18/20			ENSP00000496983.1	A0A3B3IRT3

Frequencies

GnomAD3 genomes

AF:

0.0773

AC:

11754

AN:

152046

Hom.:

629

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0204

Gnomad AMI

AF:

0.115

Gnomad AMR

AF:

0.0669

Gnomad ASJ

AF:

0.173

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0187

Gnomad FIN

AF:

0.0721

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.119

Gnomad OTH

AF:

0.0915

GnomAD3 exomes

AF:

0.0815

AC:

20269

AN:

248602

Hom.:

1154

AF XY:

0.0815

AC XY:

10991

AN XY:

134884

show subpopulations

Gnomad AFR exome

AF:

0.0187

Gnomad AMR exome

AF:

0.0534

Gnomad ASJ exome

AF:

0.176

Gnomad EAS exome

AF:

0.000167

Gnomad SAS exome

AF:

0.0243

Gnomad FIN exome

AF:

0.0723

Gnomad NFE exome

AF:

0.119

Gnomad OTH exome

AF:

0.107

GnomAD4 exome

AF:

0.105

AC:

152978

AN:

1456956

Hom.:

9146

Cov.:

AF XY:

0.103

AC XY:

74847

AN XY:

724938

show subpopulations

Gnomad4 AFR exome

AF:

0.0191

Gnomad4 AMR exome

AF:

0.0563

Gnomad4 ASJ exome

AF:

0.176

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0247

Gnomad4 FIN exome

AF:

0.0728

Gnomad4 NFE exome

AF:

0.120

Gnomad4 OTH exome

AF:

0.104

GnomAD4 genome

AF:

0.0772

AC:

11753

AN:

152164

Hom.:

629

Cov.:

AF XY:

0.0713

AC XY:

5304

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0204

Gnomad4 AMR

AF:

0.0669

Gnomad4 ASJ

AF:

0.173

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0185

Gnomad4 FIN

AF:

0.0721

Gnomad4 NFE

AF:

0.119

Gnomad4 OTH

AF:

0.0915

Alfa

AF:

0.114

Hom.:

2199

Bravo

AF:

0.0774

TwinsUK

AF:

0.110

AC:

407

ALSPAC

AF:

0.131

AC:

506

ESP6500AA

AF:

0.0209

AC:

ESP6500EA

AF:

0.120

AC:

979

ExAC

AF:

0.0817

AC:

9862

Asia WGS

AF:

0.0120

AC:

AN:

3472

EpiCase

AF:

0.127

EpiControl

AF:

0.128

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

0.084

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

.;.;.;T

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.058

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.88

D;D;D;D

MetaRNN

Benign

0.0016

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

.;.;.;M

MutationTaster

Benign

0.19

P;P;P;P

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.9

.;N;N;N

REVEL

Benign

0.098

Sift

Benign

0.12

.;T;T;T

Sift4G

Benign

0.084

.;T;T;T

Polyphen

0.79, 0.26, 0.17

.;P;B;B

Vest4

0.39, 0.41, 0.15

MPC

0.35

ClinPred

0.012

GERP RS

3.9

Varity_R

0.056

gMVP

0.28

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