13-75292232-A-G

Position:

chr13-75292232-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014832.5(TBC1D4):c.3356T>C(p.Val1119Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000964 in 1,613,178 control chromosomes in the GnomAD database, including 10 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 0.0054 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 3 hom. )

Consequence

TBC1D4
NM_014832.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 7.15

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=0.010081887).

BP6

Variant 13-75292232-A-G is Benign according to our data. Variant chr13-75292232-A-G is described in ClinVar as [Benign]. Clinvar id is 130544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00538 (819/152298) while in subpopulation AFR AF= 0.0186 (775/41570). AF 95% confidence interval is 0.0176. There are 7 homozygotes in gnomad4. There are 401 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D4	NM_014832.5 linkuse as main transcript	c.3356T>C	p.Val1119Ala	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.3356T>C	p.Val1119Ala	missense_variant	19/21	2	NM_014832.5	ENSP00000366863.3	O60343-1
TBC1D4	ENST00000431480.6 linkuse as main transcript	c.3332T>C	p.Val1111Ala	missense_variant	18/20	1		ENSP00000395986.2	O60343-3
TBC1D4	ENST00000377625.6 linkuse as main transcript	c.3167T>C	p.Val1056Ala	missense_variant	17/19	1		ENSP00000366852.2	O60343-2
TBC1D4	ENST00000648194.1 linkuse as main transcript	c.2624T>C	p.Val875Ala	missense_variant	18/20			ENSP00000496983.1	A0A3B3IRT3

Frequencies

GnomAD3 genomes

AF:

0.00536

AC:

816

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0186

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

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:

0.00334

GnomAD3 exomes

AF:

0.00137

AC:

340

AN:

248706

Hom.:

AF XY:

0.00102

AC XY:

138

AN XY:

134950

show subpopulations

Gnomad AFR exome

AF:

0.0194

Gnomad AMR exome

AF:

0.000902

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.000996

GnomAD4 exome

AF:

0.000504

AC:

736

AN:

1460880

Hom.:

Cov.:

AF XY:

0.000425

AC XY:

309

AN XY:

726776

show subpopulations

Gnomad4 AFR exome

AF:

0.0175

Gnomad4 AMR exome

AF:

0.00121

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.00123

GnomAD4 genome

AF:

0.00538

AC:

819

AN:

152298

Hom.:

Cov.:

AF XY:

0.00539

AC XY:

401

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0186

Gnomad4 AMR

AF:

0.00235

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:

0.00331

Alfa

AF:

0.00105

Hom.:

Bravo

AF:

0.00611

ESP6500AA

AF:

0.0159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00164

AC:

198

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 31, 2018	- -

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. -

TBC1D4-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2024

This variant is classified as 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

Pathogenic

0.58

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

.;.;.;T

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D;D

MetaRNN

Benign

0.010

T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.3

.;.;.;M

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.8

.;D;D;D

REVEL

Uncertain

0.42

Sift

Uncertain

0.0050

.;D;D;D

Sift4G

Pathogenic

0.0010

.;D;D;D

Polyphen

1.0

.;D;D;D

Vest4

0.76, 0.75, 0.74

MVP

0.83

MPC

1.2

ClinPred

0.029

GERP RS

5.4

Varity_R

0.55

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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