13-75287038-GA-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014832.5(TBC1D4):c.3664-14del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000654 in 1,604,286 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: TBC1D4 NM_014832.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.365

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D4	NM_014832.5	c.3664-14del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000377636.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D4	ENST00000377636.8	c.3664-14del		splice_polypyrimidine_tract_variant, intron_variant		2	NM_014832.5	A1
TBC1D4	ENST00000377625.6	c.3475-14del		splice_polypyrimidine_tract_variant, intron_variant		1		A1
TBC1D4	ENST00000431480.6	c.3640-14del		splice_polypyrimidine_tract_variant, intron_variant		1		P3
TBC1D4	ENST00000648194.1	c.2932-14del		splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.0000857 AC: 13 AN: 151766 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.0000812 AC: 20 AN: 246450 Hom.: 0 AF XY: 0.0000523 AC XY: 7 AN XY: 133962

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000223

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.0000905

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000633 AC: 92 AN: 1452402 Hom.: 0 Cov.: 29 AF XY: 0.0000608 AC XY: 44 AN XY: 723104

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000897

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000698

Gnomad4 OTH exome AF: 0.0000500

GnomAD4 genome AF: 0.0000856 AC: 13 AN: 151884 Hom.: 0 Cov.: 29 AF XY: 0.0000943 AC XY: 7 AN XY: 74206

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.0000411 Hom.: 73

Bravo AF: 0.000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs35186786; hg19: chr13-75861174;