NM_014832.5:c.2383+1098C>A

Variant names:

• chr13-75311640-G-T
• rs10492446
• NM_014832.5:c.2383+1098C>A

Variant summary

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

The NM_014832.5(TBC1D4):​c.2383+1098C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0515 in 152,122 control chromosomes in the GnomAD database, including 523 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 0.052 (523 hom., cov: 32)
• Consequence: TBC1D4 NM_014832.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.157
• Publications: 0 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

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.2383+1098C>A		intron	N/A	NP_055647.2
	TBC1D4	NM_001286658.2		c.2359+1098C>A		intron	N/A	NP_001273587.1
	TBC1D4	NM_001286659.2		c.2194+1098C>A		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.2383+1098C>A		intron	N/A	ENSP00000366863.3
	TBC1D4	ENST00000431480.6	TSL:1	c.2359+1098C>A		intron	N/A	ENSP00000395986.2
	TBC1D4	ENST00000377625.6	TSL:1	c.2194+1098C>A		intron	N/A	ENSP00000366852.2

Frequencies

GnomAD3 genomes AF: 0.0511 AC: 7772 AN: 152004 Hom.: 508 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0236

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0512

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.0340

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

GnomAD4 genome AF: 0.0515 AC: 7835 AN: 152122 Hom.: 523 Cov.: 32 AF XY: 0.0500 AC XY: 3718 AN XY: 74392

African (AFR) AF: 0.150 AC: 6219 AN: 41482

American (AMR) AF: 0.0236 AC: 360 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00721 AC: 25 AN: 3468

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5176

South Asian (SAS) AF: 0.0514 AC: 248 AN: 4824

European-Finnish (FIN) AF: 0.0114 AC: 121 AN: 10582

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0114 AC: 774 AN: 67990

Other (OTH) AF: 0.0388 AC: 82 AN: 2112

Alfa AF: 0.0456 Hom.: 54

Bravo AF: 0.0537

Asia WGS AF: 0.0610 AC: 213 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.1
DANN	Benign	0.38
PhyloP100		-0.16
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: rs10492446; hg19: chr13-75885776;