chr13-75287038-GA-G

Variant names:

• chr13-75287038-GA-G
• rs35186786
• NM_014832.5:c.3664-14delT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014832.5(TBC1D4):​c.3664-14delT variant causes a 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 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.365
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014832.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D4	NM_014832.5	MANE Select	c.3664-14delT		intron	N/A	NP_055647.2
	TBC1D4	NM_001286658.2		c.3640-14delT		intron	N/A	NP_001273587.1
	TBC1D4	NM_001286659.2		c.3475-14delT		intron	N/A	NP_001273588.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D4	ENST00000377636.8	TSL:2 MANE Select	c.3664-14delT		intron	N/A	ENSP00000366863.3
	TBC1D4	ENST00000431480.6	TSL:1	c.3640-14delT		intron	N/A	ENSP00000395986.2
	TBC1D4	ENST00000377625.6	TSL:1	c.3475-14delT		intron	N/A	ENSP00000366852.2

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

GnomAD2 exomes AF: 0.0000812 AC: 20 AN: 246450 AF XY: 0.0000523

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33196

American (AMR) AF: 0.0000897 AC: 4 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39630

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86082

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.0000698 AC: 77 AN: 1103624

Other (OTH) AF: 0.0000500 AC: 3 AN: 60056

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

African (AFR) AF: 0.0000484 AC: 2 AN: 41348

American (AMR) AF: 0.0000656 AC: 1 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67970

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.0000411 Hom.: 73

Bravo AF: 0.000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs35186786; hg19: chr13-75861174; COSMIC: COSV66490333;