13-75286865-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_014832.5(TBC1D4):c.3824T>C(p.Val1275Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0749 in 1,613,742 control chromosomes in the GnomAD database, including 12,177 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.18 (5386 hom., cov: 32)
  • Exomes 𝑓: 0.064 (6791 hom.)
• Consequence: TBC1D4 NM_014832.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.43

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.917383E-4).
• BP6: Variant 13-75286865-A-G is Benign according to our data. Variant chr13-75286865-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 130861.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D4	NM_014832.5	c.3824T>C	p.Val1275Ala	missense_variant	21/21	ENST00000377636.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D4	ENST00000377636.8	c.3824T>C	p.Val1275Ala	missense_variant	21/21	2	NM_014832.5	A1
TBC1D4	ENST00000431480.6	c.3800T>C	p.Val1267Ala	missense_variant	20/20	1		P3
TBC1D4	ENST00000377625.6	c.3635T>C	p.Val1212Ala	missense_variant	19/19	1		A1
TBC1D4	ENST00000648194.1	c.3092T>C	p.Val1031Ala	missense_variant	20/20

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27099 AN: 151958 Hom.: 5365 Cov.: 32

Gnomad AFR AF: 0.492

Gnomad AMI AF: 0.0901

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.0672

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0155

Gnomad FIN AF: 0.0461

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0593

Gnomad OTH AF: 0.147

GnomAD3 exomes AF: 0.0749 AC: 18650 AN: 249138 Hom.: 2339 AF XY: 0.0661 AC XY: 8937 AN XY: 135182

Gnomad AFR exome AF: 0.504

Gnomad AMR exome AF: 0.0545

Gnomad ASJ exome AF: 0.0646

Gnomad EAS exome AF: 0.000334

Gnomad SAS exome AF: 0.0145

Gnomad FIN exome AF: 0.0413

Gnomad NFE exome AF: 0.0584

Gnomad OTH exome AF: 0.0636

GnomAD4 exome AF: 0.0641 AC: 93712 AN: 1461666 Hom.: 6791 Cov.: 32 AF XY: 0.0611 AC XY: 44436 AN XY: 727132

Gnomad4 AFR exome AF: 0.509

Gnomad4 AMR exome AF: 0.0597

Gnomad4 ASJ exome AF: 0.0636

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0153

Gnomad4 FIN exome AF: 0.0435

Gnomad4 NFE exome AF: 0.0572

Gnomad4 OTH exome AF: 0.0767

GnomAD4 genome AF: 0.179 AC: 27163 AN: 152076 Hom.: 5386 Cov.: 32 AF XY: 0.173 AC XY: 12881 AN XY: 74354

Gnomad4 AFR AF: 0.492

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.0672

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0151

Gnomad4 FIN AF: 0.0461

Gnomad4 NFE AF: 0.0593

Gnomad4 OTH AF: 0.145

Alfa AF: 0.0761 Hom.: 2809

Bravo AF: 0.194

TwinsUK AF: 0.0596 AC: 221

ALSPAC AF: 0.0550 AC: 212

ESP6500AA AF: 0.462 AC: 1770

ESP6500EA AF: 0.0586 AC: 484

ExAC AF: 0.0830 AC: 10026

Asia WGS AF: 0.0400 AC: 137 AN: 3478

EpiCase AF: 0.0592

EpiControl AF: 0.0603

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	6.9
Dann	Benign	0.25
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.035	T;T;T;T
MetaRNN	Benign	0.00049	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.41	T
Polyphen		0.0	.;B;B;B
Vest4		0.024, 0.026, 0.0080
MPC		0.40
ClinPred		0.0055	T
GERP RS		3.9
Varity_R		0.012
gMVP		0.23

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: rs557337; hg19: chr13-75861001; COSMIC: COSV66493282;