rs1062087

Variant names:

Variant summary

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

The NM_014832.5(TBC1D4):c.2455G>A(p.Val819Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.855 in 1,613,816 control chromosomes in the GnomAD database, including 597,291 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.75 ( 45590 hom., cov: 31)

Exomes 𝑓: 0.87 ( 551701 hom. )

Consequence

TBC1D4
NM_014832.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0320

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=6.2582626E-7).

BP6

Variant 13-75310080-C-T is Benign according to our data. Variant chr13-75310080-C-T is described in ClinVar as [Benign]. Clinvar id is 130549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D4	NM_014832.5 link	c.2455G>A	p.Val819Ile	missense_variant	Exon 14 of 21	ENST00000377636.8	NP_055647.2	O60343-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D4	ENST00000377636.8 link	c.2455G>A	p.Val819Ile	missense_variant	Exon 14 of 21	2	NM_014832.5	ENSP00000366863.3		O60343-1

Frequencies

GnomAD3 genomes

AF:

0.754

AC:

114515

AN:

151926

Hom.:

45563

Cov.:

show subpopulations

Gnomad AFR

AF:

0.485

Gnomad AMI

AF:

0.989

Gnomad AMR

AF:

0.718

Gnomad ASJ

AF:

0.859

Gnomad EAS

AF:

0.809

Gnomad SAS

AF:

0.928

Gnomad FIN

AF:

0.831

Gnomad MID

AF:

0.835

Gnomad NFE

AF:

0.888

Gnomad OTH

AF:

0.763

GnomAD3 exomes

AF:

0.825

AC:

205472

AN:

249084

Hom.:

86445

AF XY:

0.841

AC XY:

113604

AN XY:

135138

show subpopulations

Gnomad AFR exome

AF:

0.477

Gnomad AMR exome

AF:

0.687

Gnomad ASJ exome

AF:

0.871

Gnomad EAS exome

AF:

0.813

Gnomad SAS exome

AF:

0.934

Gnomad FIN exome

AF:

0.825

Gnomad NFE exome

AF:

0.882

Gnomad OTH exome

AF:

0.839

GnomAD4 exome

AF:

0.865

AC:

1265080

AN:

1461772

Hom.:

551701

Cov.:

AF XY:

0.870

AC XY:

632502

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.468

Gnomad4 AMR exome

AF:

0.691

Gnomad4 ASJ exome

AF:

0.872

Gnomad4 EAS exome

AF:

0.779

Gnomad4 SAS exome

AF:

0.933

Gnomad4 FIN exome

AF:

0.822

Gnomad4 NFE exome

AF:

0.885

Gnomad4 OTH exome

AF:

0.845

GnomAD4 genome

AF:

0.754

AC:

114588

AN:

152044

Hom.:

45590

Cov.:

AF XY:

0.753

AC XY:

56006

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.485

Gnomad4 AMR

AF:

0.717

Gnomad4 ASJ

AF:

0.859

Gnomad4 EAS

AF:

0.809

Gnomad4 SAS

AF:

0.928

Gnomad4 FIN

AF:

0.831

Gnomad4 NFE

AF:

0.888

Gnomad4 OTH

AF:

0.766

Alfa

AF:

0.863

Hom.:

139234

Bravo

AF:

0.732

TwinsUK

AF:

0.890

AC:

3299

ALSPAC

AF:

0.891

AC:

3433

ESP6500AA

AF:

0.504

AC:

1880

ESP6500EA

AF:

0.884

AC:

7236

ExAC

AF:

0.825

AC:

99680

Asia WGS

AF:

0.835

AC:

2904

AN:

3478

EpiCase

AF:

0.887

EpiControl

AF:

0.882

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

5.4

DANN

Benign

0.76

DEOGEN2

Benign

0.024

.;.;.;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.018

T;T;T;T;T

MetaRNN

Benign

6.3e-7

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

.;.;.;N;.

PrimateAI

Benign

0.39

PROVEAN

Benign

0.020

.;N;N;N;N

REVEL

Benign

0.057

Sift

Benign

0.32

.;T;T;T;T

Sift4G

Benign

0.59

.;T;T;T;.

Polyphen

0.0

.;B;B;B;.

Vest4

0.051, 0.024, 0.0090

MPC

0.27

ClinPred

0.0027

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.011

gMVP

0.034

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