13-75292518-T-A

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D4	NM_014832.5	c.3317-247A>T		intron_variant		ENST00000377636.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D4	ENST00000377636.8	c.3317-247A>T		intron_variant		2	NM_014832.5	A1
TBC1D4	ENST00000377625.6	c.3128-247A>T		intron_variant		1		A1
TBC1D4	ENST00000431480.6	c.3293-247A>T		intron_variant		1		P3
TBC1D4	ENST00000648194.1	c.2585-247A>T		intron_variant

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

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.347

Gnomad4 ASJ AF: 0.442

Gnomad4 EAS AF: 0.104

Gnomad4 SAS AF: 0.250

Gnomad4 FIN AF: 0.455

Gnomad4 NFE AF: 0.381

Gnomad4 OTH AF: 0.310

Alfa AF: 0.333 Hom.: 1140

Bravo AF: 0.287

Asia WGS AF: 0.182 AC: 629 AN: 3452

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.6
Dann	Benign	0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs9600456; hg19: chr13-75866654;