rs386379791

chr13-75287038-G-GAchr13-75287038-GA-Gchr13-75287038-G-GAA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_014832.5(TBC1D4):c.3664-14_3664-13insT variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0758 in 1,604,062 control chromosomes in the GnomAD database, including 12,758 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (5680 hom., cov: 29)
  • Exomes 𝑓: 0.065 (7078 hom.)
• Consequence: TBC1D4 NM_014832.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.365

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 -10 ACMG points.

• BP6: Variant 13-75287038-G-GA is Benign according to our data. Variant chr13-75287038-G-GA is described in ClinVar as [Benign]. Clinvar id is 212373.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D4	NM_014832.5	c.3664-14_3664-13insT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000377636.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D4	ENST00000377636.8	c.3664-14_3664-13insT		splice_polypyrimidine_tract_variant, intron_variant		2	NM_014832.5	A1
TBC1D4	ENST00000377625.6	c.3475-14_3475-13insT		splice_polypyrimidine_tract_variant, intron_variant		1		A1
TBC1D4	ENST00000431480.6	c.3640-14_3640-13insT		splice_polypyrimidine_tract_variant, intron_variant		1		P3
TBC1D4	ENST00000648194.1	c.2932-14_2932-13insT		splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27698 AN: 151716 Hom.: 5658 Cov.: 29

Gnomad AFR AF: 0.507

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.0675

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0156

Gnomad FIN AF: 0.0464

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0595

Gnomad OTH AF: 0.150

GnomAD3 exomes AF: 0.0764 AC: 18837 AN: 246450 Hom.: 2439 AF XY: 0.0672 AC XY: 9006 AN XY: 133962

Gnomad AFR exome AF: 0.519

Gnomad AMR exome AF: 0.0560

Gnomad ASJ exome AF: 0.0645

Gnomad EAS exome AF: 0.000334

Gnomad SAS exome AF: 0.0150

Gnomad FIN exome AF: 0.0420

Gnomad NFE exome AF: 0.0588

Gnomad OTH exome AF: 0.0643

GnomAD4 exome AF: 0.0646 AC: 93787 AN: 1452228 Hom.: 7078 Cov.: 29 AF XY: 0.0616 AC XY: 44535 AN XY: 723024

Gnomad4 AFR exome AF: 0.523

Gnomad4 AMR exome AF: 0.0606

Gnomad4 ASJ exome AF: 0.0634

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0157

Gnomad4 FIN exome AF: 0.0445

Gnomad4 NFE exome AF: 0.0573

Gnomad4 OTH exome AF: 0.0777

GnomAD4 genome AF: 0.183 AC: 27763 AN: 151834 Hom.: 5680 Cov.: 29 AF XY: 0.178 AC XY: 13173 AN XY: 74176

Gnomad4 AFR AF: 0.507

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.0675

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0152

Gnomad4 FIN AF: 0.0464

Gnomad4 NFE AF: 0.0595

Gnomad4 OTH AF: 0.148

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 21, 2013

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs35186786; hg19: chr13-75861174;