13-75292245-C-T

Variant names:

• chr13-75292245-C-T
• rs1349812447
• NM_014832.5:c.3343G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014832.5(TBC1D4):​c.3343G>A​(p.Val1115Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TBC1D4 NM_014832.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31014878).

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.3343G>A	p.Val1115Ile	missense	Exon 19 of 21	NP_055647.2	O60343-1
	TBC1D4	NM_001286658.2		c.3319G>A	p.Val1107Ile	missense	Exon 18 of 20	NP_001273587.1	O60343-3
	TBC1D4	NM_001286659.2		c.3154G>A	p.Val1052Ile	missense	Exon 17 of 19	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.3343G>A	p.Val1115Ile	missense	Exon 19 of 21	ENSP00000366863.3	O60343-1
	TBC1D4	ENST00000431480.6	TSL:1	c.3319G>A	p.Val1107Ile	missense	Exon 18 of 20	ENSP00000395986.2	O60343-3
	TBC1D4	ENST00000377625.6	TSL:1	c.3154G>A	p.Val1052Ile	missense	Exon 17 of 19	ENSP00000366852.2	O60343-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000805 AC: 2 AN: 248330 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460470 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726554

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.0000448 AC: 2 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.00 AC: 0 AN: 86088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111412

Other (OTH) AF: 0.00 AC: 0 AN: 60342

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.6
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.15
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.036	D
Polyphen		0.98	D
Vest4		0.35
MutPred		0.49		Gain of catalytic residue at A1120 (P = 0)
MVP		0.55
MPC		0.65
ClinPred		0.68	D
GERP RS		5.4
Varity_R		0.24
gMVP		0.30
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1349812447; hg19: chr13-75866381;