13-75292518-T-A

Variant names:

• chr13-75292518-T-A
• rs9600456
• NM_014832.5:c.3317-247A>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014832.5(TBC1D4):​c.3317-247A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 152,002 control chromosomes in the GnomAD database, including 8,077 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.30 (8077 hom., cov: 32)
• Consequence: TBC1D4 NM_014832.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.289
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 13-75292518-T-A is Benign according to our data. Variant chr13-75292518-T-A is described in ClinVar as Benign. ClinVar VariationId is 1279343.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.377 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D4	NM_014832.5	MANE Select	c.3317-247A>T		intron	N/A	NP_055647.2	O60343-1
	TBC1D4	NM_001286658.2		c.3293-247A>T		intron	N/A	NP_001273587.1	O60343-3
	TBC1D4	NM_001286659.2		c.3128-247A>T		intron	N/A	NP_001273588.1	O60343-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D4	ENST00000377636.8	TSL:2 MANE Select	c.3317-247A>T		intron	N/A	ENSP00000366863.3	O60343-1
	TBC1D4	ENST00000431480.6	TSL:1	c.3293-247A>T		intron	N/A	ENSP00000395986.2	O60343-3
	TBC1D4	ENST00000377625.6	TSL:1	c.3128-247A>T		intron	N/A	ENSP00000366852.2	O60343-2

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45356 AN: 151884 Hom.: 8076 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.347

Gnomad ASJ AF: 0.442

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.455

Gnomad MID AF: 0.299

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.309

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

GnomAD4 genome AF: 0.298 AC: 45372 AN: 152002 Hom.: 8077 Cov.: 32 AF XY: 0.300 AC XY: 22287 AN XY: 74276

African (AFR) AF: 0.118 AC: 4892 AN: 41538

American (AMR) AF: 0.347 AC: 5307 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.442 AC: 1533 AN: 3466

East Asian (EAS) AF: 0.104 AC: 541 AN: 5180

South Asian (SAS) AF: 0.250 AC: 1205 AN: 4820

European-Finnish (FIN) AF: 0.455 AC: 4764 AN: 10478

Middle Eastern (MID) AF: 0.291 AC: 85 AN: 292

European-Non Finnish (NFE) AF: 0.381 AC: 25889 AN: 67926

Other (OTH) AF: 0.310 AC: 655 AN: 2114

Alfa AF: 0.333 Hom.: 1140

Bravo AF: 0.287

Asia WGS AF: 0.182 AC: 629 AN: 3452

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.6
DANN	Benign	0.47
PhyloP100		0.29
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: rs9600456; hg19: chr13-75866654;