rs386379791
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_014832.5(TBC1D4):c.3664-14_3664-13insTT 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 0.0000132 in 151,766 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 0.000013 ( 0 hom., cov: 29)
Consequence
TBC1D4
NM_014832.5 splice_polypyrimidine_tract, intron
NM_014832.5 splice_polypyrimidine_tract, intron
Scores
Not classified
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]
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ACMG classification
Classification made for transcript
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.3664-14_3664-13insTT | splice_polypyrimidine_tract_variant, intron_variant | ENST00000377636.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TBC1D4 | ENST00000377636.8 | c.3664-14_3664-13insTT | splice_polypyrimidine_tract_variant, intron_variant | 2 | NM_014832.5 | A1 | |||
TBC1D4 | ENST00000377625.6 | c.3475-14_3475-13insTT | splice_polypyrimidine_tract_variant, intron_variant | 1 | A1 | ||||
TBC1D4 | ENST00000431480.6 | c.3640-14_3640-13insTT | splice_polypyrimidine_tract_variant, intron_variant | 1 | P3 | ||||
TBC1D4 | ENST00000648194.1 | c.2932-14_2932-13insTT | splice_polypyrimidine_tract_variant, intron_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151766Hom.: 0 Cov.: 29
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GnomAD4 exome Cov.: 29
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GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151766Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1AN XY: 74078
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at