rs1560540

Variant names:

• chr13-75308359-A-G
• rs1560540
• NM_014832.5:c.2593+1583T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014832.5(TBC1D4):​c.2593+1583T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 151,998 control chromosomes in the GnomAD database, including 13,670 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 0.41 (13670 hom., cov: 31)
• Consequence: TBC1D4 NM_014832.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.28
• Publications: 5 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D4	NM_014832.5	c.2593+1583T>C		intron_variant	Intron 14 of 20	ENST00000377636.8	NP_055647.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D4	ENST00000377636.8	c.2593+1583T>C		intron_variant	Intron 14 of 20	2	NM_014832.5	ENSP00000366863.3

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61718 AN: 151880 Hom.: 13662 Cov.: 31

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.621

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.595

Gnomad SAS AF: 0.649

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.399

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

GnomAD4 genome AF: 0.406 AC: 61740 AN: 151998 Hom.: 13670 Cov.: 31 AF XY: 0.410 AC XY: 30447 AN XY: 74266

African (AFR) AF: 0.248 AC: 10298 AN: 41462

American (AMR) AF: 0.300 AC: 4580 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1854 AN: 3470

East Asian (EAS) AF: 0.595 AC: 3074 AN: 5164

South Asian (SAS) AF: 0.647 AC: 3109 AN: 4806

European-Finnish (FIN) AF: 0.485 AC: 5119 AN: 10556

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.473 AC: 32154 AN: 67952

Other (OTH) AF: 0.406 AC: 857 AN: 2112

Alfa AF: 0.435 Hom.: 2385

Bravo AF: 0.383

Asia WGS AF: 0.604 AC: 2099 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.3
DANN	Benign	0.47
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1560540; hg19: chr13-75882495; COSMIC: COSV66491529; COSMIC: COSV66491529;