13-75465240-T-C

Position:

• chr13-75465240-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014832.5(TBC1D4):​c.498+16030A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0498 in 152,268 control chromosomes in the GnomAD database, including 378 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.050 (378 hom., cov: 32)
• Consequence: TBC1D4 NM_014832.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.242

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D4	NM_014832.5	c.498+16030A>G		intron_variant		ENST00000377636.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D4	ENST00000377636.8	c.498+16030A>G		intron_variant		2	NM_014832.5	A1
TBC1D4	ENST00000377625.6	c.498+16030A>G		intron_variant		1		A1
TBC1D4	ENST00000431480.6	c.498+16030A>G		intron_variant		1		P3

Frequencies

GnomAD3 genomes AF: 0.0499 AC: 7585 AN: 152150 Hom.: 378 Cov.: 32

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.0451

Gnomad ASJ AF: 0.0818

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.0938

Gnomad FIN AF: 0.0283

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0578

Gnomad OTH AF: 0.0645

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0498 AC: 7582 AN: 152268 Hom.: 378 Cov.: 32 AF XY: 0.0492 AC XY: 3665 AN XY: 74456

Gnomad4 AFR AF: 0.0120

Gnomad4 AMR AF: 0.0449

Gnomad4 ASJ AF: 0.0818

Gnomad4 EAS AF: 0.234

Gnomad4 SAS AF: 0.0940

Gnomad4 FIN AF: 0.0283

Gnomad4 NFE AF: 0.0578

Gnomad4 OTH AF: 0.0639

Alfa AF: 0.0587 Hom.: 410

Bravo AF: 0.0504

Asia WGS AF: 0.141 AC: 490 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	13
DANN	Benign	0.77

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: rs9565164; hg19: chr13-76039376;