chr13-75299651-G-A

Position:

• chr13-75299651-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014832.5(TBC1D4):​c.2912-77C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 1,547,502 control chromosomes in the GnomAD database, including 222,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18427 hom., cov: 29)
  • Exomes 𝑓: 0.53 (203806 hom.)
• Consequence: TBC1D4 NM_014832.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00100

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 13-75299651-G-A is Benign according to our data. Variant chr13-75299651-G-A is described in ClinVar as [Benign]. Clinvar id is 1271807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D4	NM_014832.5	c.2912-77C>T		intron_variant		ENST00000377636.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D4	ENST00000377636.8	c.2912-77C>T		intron_variant		2	NM_014832.5	A1

Frequencies

GnomAD3 genomes AF: 0.484 AC: 73308 AN: 151442 Hom.: 18416 Cov.: 29

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.623

Gnomad AMR AF: 0.491

Gnomad ASJ AF: 0.597

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.420

Gnomad FIN AF: 0.581

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.551

Gnomad OTH AF: 0.478

GnomAD4 exome AF: 0.534 AC: 744764 AN: 1395946 Hom.: 203806 AF XY: 0.531 AC XY: 369628 AN XY: 695574

Gnomad4 AFR exome AF: 0.387

Gnomad4 AMR exome AF: 0.499

Gnomad4 ASJ exome AF: 0.600

Gnomad4 EAS exome AF: 0.118

Gnomad4 SAS exome AF: 0.429

Gnomad4 FIN exome AF: 0.588

Gnomad4 NFE exome AF: 0.560

Gnomad4 OTH exome AF: 0.515

GnomAD4 genome AF: 0.484 AC: 73352 AN: 151556 Hom.: 18427 Cov.: 29 AF XY: 0.480 AC XY: 35481 AN XY: 73986

Gnomad4 AFR AF: 0.388

Gnomad4 AMR AF: 0.491

Gnomad4 ASJ AF: 0.597

Gnomad4 EAS AF: 0.118

Gnomad4 SAS AF: 0.420

Gnomad4 FIN AF: 0.581

Gnomad4 NFE AF: 0.551

Gnomad4 OTH AF: 0.481

Alfa AF: 0.535 Hom.: 37604

Bravo AF: 0.475

Asia WGS AF: 0.315 AC: 1095 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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.8
DANN	Benign	0.73

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: rs2297207; hg19: chr13-75873787;