NM_014832.5:c.3664-14dupT

Variant names:

• chr13-75287038-G-GA
• rs35186786
• NM_014832.5:c.3664-14dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_014832.5(TBC1D4):​c.3664-14dupT variant causes a 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 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.365
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014832.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D4	NM_014832.5	MANE Select	c.3664-14dupT		intron	N/A	NP_055647.2	O60343-1
	TBC1D4	NM_001286658.2		c.3640-14dupT		intron	N/A	NP_001273587.1	O60343-3
	TBC1D4	NM_001286659.2		c.3475-14dupT		intron	N/A	NP_001273588.1	O60343-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D4	ENST00000377636.8	TSL:2 MANE Select	c.3664-14_3664-13insT		intron	N/A	ENSP00000366863.3	O60343-1
	TBC1D4	ENST00000431480.6	TSL:1	c.3640-14_3640-13insT		intron	N/A	ENSP00000395986.2	O60343-3
	TBC1D4	ENST00000377625.6	TSL:1	c.3475-14_3475-13insT		intron	N/A	ENSP00000366852.2	O60343-2

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

GnomAD2 exomes AF: 0.0764 AC: 18837 AN: 246450 AF XY: 0.0672

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 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

African (AFR) AF: 0.523 AC: 17353 AN: 33190

American (AMR) AF: 0.0606 AC: 2703 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.0634 AC: 1654 AN: 26080

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39630

South Asian (SAS) AF: 0.0157 AC: 1349 AN: 86078

European-Finnish (FIN) AF: 0.0445 AC: 2374 AN: 53374

Middle Eastern (MID) AF: 0.0879 AC: 505 AN: 5744

European-Non Finnish (NFE) AF: 0.0573 AC: 63176 AN: 1103466

Other (OTH) AF: 0.0777 AC: 4664 AN: 60054

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

African (AFR) AF: 0.507 AC: 20946 AN: 41322

American (AMR) AF: 0.102 AC: 1549 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.0675 AC: 234 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.0152 AC: 73 AN: 4806

European-Finnish (FIN) AF: 0.0464 AC: 489 AN: 10542

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0595 AC: 4044 AN: 67960

Other (OTH) AF: 0.148 AC: 313 AN: 2110

Alfa AF: 0.0441 Hom.: 73

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35186786; hg19: chr13-75861174;