13-75292148-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 4.70

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]

ACMG classification

Verdict is Benign. Variant got -14 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_single_submitter, 1 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	UniProt
TBC1D4	NM_014832.5	c.3440C>T	p.Thr1147Met	missense_variant	19/21	ENST00000377636.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D4	ENST00000377636.8	c.3440C>T	p.Thr1147Met	missense_variant	19/21	2	NM_014832.5	A1
TBC1D4	ENST00000431480.6	c.3416C>T	p.Thr1139Met	missense_variant	18/20	1		P3
TBC1D4	ENST00000377625.6	c.3251C>T	p.Thr1084Met	missense_variant	17/19	1		A1
TBC1D4	ENST00000648194.1	c.2708C>T	p.Thr903Met	missense_variant	18/20

Frequencies

GnomAD3 genomes AF: 0.0773 AC: 11754 AN: 152046 Hom.: 629 Cov.: 32

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

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.: 31 AF XY: 0.103 AC XY: 74847 AN XY: 724938

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.: 32 AF XY: 0.0713 AC XY: 5304 AN XY: 74370

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: 76

ESP6500EA AF: 0.120 AC: 979

ExAC AF: 0.0817 AC: 9862

Asia WGS AF: 0.0120 AC: 43 AN: 3472

EpiCase AF: 0.127

EpiControl AF: 0.128

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	22
Dann	Uncertain	0.98
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.058
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D;D;D;D
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.19	P;P;P;P
PrimateAI	Benign	0.48	T
Polyphen		0.79, 0.26, 0.17	.;P;B;B
Vest4		0.39, 0.41, 0.15
MPC		0.35
ClinPred		0.012	T
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

Other links and lift over

dbSNP: rs9600455; hg19: chr13-75866284; COSMIC: COSV66489352; COSMIC: COSV66489352;