rs1062087

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

Publications

37 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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

GnomAD2 exomes

AF:

0.825

AC:

205472

AN:

249084

AF XY:

0.841

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 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

African (AFR)

AF:

0.468

AC:

15661

AN:

33478

American (AMR)

AF:

0.691

AC:

30907

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.872

AC:

22792

AN:

26136

East Asian (EAS)

AF:

0.779

AC:

30912

AN:

39700

South Asian (SAS)

AF:

0.933

AC:

80434

AN:

86252

European-Finnish (FIN)

AF:

0.822

AC:

43894

AN:

53402

Middle Eastern (MID)

AF:

0.877

AC:

5056

AN:

5766

European-Non Finnish (NFE)

AF:

0.885

AC:

984374

AN:

1111940

Other (OTH)

AF:

0.845

AC:

51050

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

9695

19390

29086

38781

48476

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21268

42536

63804

85072

106340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.754

AC:

114588

AN:

152044

Hom.:

45590

Cov.:

AF XY:

0.753

AC XY:

56006

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.485

AC:

20085

AN:

41410

American (AMR)

AF:

0.717

AC:

10954

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.859

AC:

2981

AN:

3472

East Asian (EAS)

AF:

0.809

AC:

4175

AN:

5158

South Asian (SAS)

AF:

0.928

AC:

4460

AN:

4804

European-Finnish (FIN)

AF:

0.831

AC:

8801

AN:

10596

Middle Eastern (MID)

AF:

0.833

AC:

245

AN:

294

European-Non Finnish (NFE)

AF:

0.888

AC:

60366

AN:

68010

Other (OTH)

AF:

0.766

AC:

1619

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1197

2394

3591

4788

5985

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

840

1680

2520

3360

4200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.848

Hom.:

245744

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

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

(source)

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;.

PhyloP100

0.032

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over