chr13-75288980-T-C

Position:

chr13-75288980-T-C

Variant summary

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

The NM_014832.5(TBC1D4):c.3617A>G(p.Asn1206Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 1,613,960 control chromosomes in the GnomAD database, including 251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 15 hom., cov: 32)

Exomes 𝑓: 0.016 ( 236 hom. )

Consequence

TBC1D4
NM_014832.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.61

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=0.0054231584).

BP6

Variant 13-75288980-T-C is Benign according to our data. Variant chr13-75288980-T-C is described in ClinVar as [Benign]. Clinvar id is 130553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-75288980-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0103 (1565/152314) while in subpopulation SAS AF= 0.0317 (153/4834). AF 95% confidence interval is 0.0276. There are 15 homozygotes in gnomad4. There are 748 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 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.3617A>G	p.Asn1206Ser	missense_variant	20/21	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.3617A>G	p.Asn1206Ser	missense_variant	20/21	2	NM_014832.5	ENSP00000366863.3	O60343-1
TBC1D4	ENST00000431480.6 linkuse as main transcript	c.3593A>G	p.Asn1198Ser	missense_variant	19/20	1		ENSP00000395986.2	O60343-3
TBC1D4	ENST00000377625.6 linkuse as main transcript	c.3428A>G	p.Asn1143Ser	missense_variant	18/19	1		ENSP00000366852.2	O60343-2
TBC1D4	ENST00000648194.1 linkuse as main transcript	c.2885A>G	p.Asn962Ser	missense_variant	19/20			ENSP00000496983.1	A0A3B3IRT3

Frequencies

GnomAD3 genomes

AF:

0.0103

AC:

1566

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00268

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00681

Gnomad ASJ

AF:

0.0277

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0314

Gnomad FIN

AF:

0.00706

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0147

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0134

AC:

3348

AN:

249288

Hom.:

AF XY:

0.0154

AC XY:

2078

AN XY:

135240

show subpopulations

Gnomad AFR exome

AF:

0.00310

Gnomad AMR exome

AF:

0.00476

Gnomad ASJ exome

AF:

0.0260

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.0320

Gnomad FIN exome

AF:

0.00561

Gnomad NFE exome

AF:

0.0148

Gnomad OTH exome

AF:

0.0164

GnomAD4 exome

AF:

0.0156

AC:

22859

AN:

1461646

Hom.:

236

Cov.:

AF XY:

0.0163

AC XY:

11841

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.00254

Gnomad4 AMR exome

AF:

0.00528

Gnomad4 ASJ exome

AF:

0.0250

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0323

Gnomad4 FIN exome

AF:

0.00580

Gnomad4 NFE exome

AF:

0.0159

Gnomad4 OTH exome

AF:

0.0165

GnomAD4 genome

AF:

0.0103

AC:

1565

AN:

152314

Hom.:

Cov.:

AF XY:

0.0100

AC XY:

748

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00267

Gnomad4 AMR

AF:

0.00674

Gnomad4 ASJ

AF:

0.0277

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0317

Gnomad4 FIN

AF:

0.00706

Gnomad4 NFE

AF:

0.0147

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0152

Hom.:

Bravo

AF:

0.0100

TwinsUK

AF:

0.0124

AC:

ALSPAC

AF:

0.0176

AC:

ESP6500AA

AF:

0.00324

AC:

ESP6500EA

AF:

0.0160

AC:

131

ExAC

AF:

0.0137

AC:

1652

Asia WGS

AF:

0.00982

AC:

AN:

3478

EpiCase

AF:

0.0170

EpiControl

AF:

0.0159

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 05, 2013

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.47

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

.;.;.;T

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;D

MetaRNN

Benign

0.0054

T;T;T;T

MetaSVM

Uncertain

0.15

MutationAssessor

Uncertain

2.9

.;.;.;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.7

.;D;D;D

REVEL

Uncertain

0.32

Sift

Uncertain

0.0020

.;D;D;D

Sift4G

Uncertain

0.017

.;D;D;D

Polyphen

1.0, 1.0, 1.0

.;D;D;D

Vest4

0.41, 0.53, 0.24

MPC

0.97

ClinPred

0.0094

GERP RS

5.3

Varity_R

0.44

gMVP

0.48

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