13-75292525-C-T

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.3317-254G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 151,984 control chromosomes in the GnomAD database, including 7,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.29 (7755 hom., cov: 31)
• Consequence: TBC1D4 NM_014832.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.53

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=-0.95).
• BP6: Variant 13-75292525-C-T is Benign according to our data. Variant chr13-75292525-C-T is described in ClinVar as [Benign]. Clinvar id is 1222510.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D4	NM_014832.5	c.3317-254G>A		intron_variant		ENST00000377636.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D4	ENST00000377636.8	c.3317-254G>A		intron_variant		2	NM_014832.5	A1
TBC1D4	ENST00000377625.6	c.3128-254G>A		intron_variant		1		A1
TBC1D4	ENST00000431480.6	c.3293-254G>A		intron_variant		1		P3
TBC1D4	ENST00000648194.1	c.2585-254G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44598 AN: 151864 Hom.: 7727 Cov.: 31

Gnomad AFR AF: 0.478

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.0123

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.271

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

GnomAD4 genome AF: 0.294 AC: 44678 AN: 151984 Hom.: 7755 Cov.: 31 AF XY: 0.285 AC XY: 21156 AN XY: 74264

Gnomad4 AFR AF: 0.478

Gnomad4 AMR AF: 0.236

Gnomad4 ASJ AF: 0.217

Gnomad4 EAS AF: 0.0124

Gnomad4 SAS AF: 0.197

Gnomad4 FIN AF: 0.170

Gnomad4 NFE AF: 0.248

Gnomad4 OTH AF: 0.272

Alfa AF: 0.272 Hom.: 1247

Bravo AF: 0.304

Asia WGS AF: 0.165 AC: 569 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

Nov 12, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	0.050
Dann	Benign	0.30

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: rs7985912; hg19: chr13-75866661; COSMIC: COSV66491489; COSMIC: COSV66491489;