chr13-75294705-C-T

Position:

• chr13-75294705-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.3316+149G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 822,658 control chromosomes in the GnomAD database, including 146,875 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.59 (26850 hom., cov: 33)
  • Exomes 𝑓: 0.59 (120025 hom.)
• Consequence: TBC1D4 NM_014832.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.12

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=-0.9).
• BP6: Variant 13-75294705-C-T is Benign according to our data. Variant chr13-75294705-C-T is described in ClinVar as [Benign]. Clinvar id is 1295485.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D4	NM_014832.5	c.3316+149G>A		intron_variant		ENST00000377636.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D4	ENST00000377636.8	c.3316+149G>A		intron_variant		2	NM_014832.5	A1
TBC1D4	ENST00000377625.6	c.3127+149G>A		intron_variant		1		A1
TBC1D4	ENST00000431480.6	c.3292+149G>A		intron_variant		1		P3
TBC1D4	ENST00000648194.1	c.2584+149G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.587 AC: 89141 AN: 151976 Hom.: 26823 Cov.: 33

Gnomad AFR AF: 0.595

Gnomad AMI AF: 0.713

Gnomad AMR AF: 0.569

Gnomad ASJ AF: 0.654

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.632

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.574

GnomAD4 exome AF: 0.586 AC: 392947 AN: 670564 Hom.: 120025 AF XY: 0.582 AC XY: 199816 AN XY: 343290

Gnomad4 AFR exome AF: 0.598

Gnomad4 AMR exome AF: 0.546

Gnomad4 ASJ exome AF: 0.659

Gnomad4 EAS exome AF: 0.119

Gnomad4 SAS exome AF: 0.459

Gnomad4 FIN exome AF: 0.638

Gnomad4 NFE exome AF: 0.625

Gnomad4 OTH exome AF: 0.579

GnomAD4 genome AF: 0.587 AC: 89221 AN: 152094 Hom.: 26850 Cov.: 33 AF XY: 0.580 AC XY: 43113 AN XY: 74346

Gnomad4 AFR AF: 0.595

Gnomad4 AMR AF: 0.570

Gnomad4 ASJ AF: 0.654

Gnomad4 EAS AF: 0.119

Gnomad4 SAS AF: 0.445

Gnomad4 FIN AF: 0.632

Gnomad4 NFE AF: 0.619

Gnomad4 OTH AF: 0.575

Alfa AF: 0.599 Hom.: 4348

Bravo AF: 0.582

Asia WGS AF: 0.340 AC: 1183 AN: 3478

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.20
DANN	Benign	0.45

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: rs4885284; hg19: chr13-75868841;