NM_014832.5:c.3356T>C

Variant names:

• chr13-75292232-A-G
• rs58232698
• NM_014832.5:c.3356T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014832.5(TBC1D4):​c.3356T>C​(p.Val1119Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000964 in 1,613,178 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (3 hom.)
• Consequence: TBC1D4 NM_014832.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.15
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010081887).
• BP6: Variant 13-75292232-A-G is Benign according to our data. Variant chr13-75292232-A-G is described in ClinVar as Benign. ClinVar VariationId is 130544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00538 (819/152298) while in subpopulation AFR AF = 0.0186 (775/41570). AF 95% confidence interval is 0.0176. There are 7 homozygotes in GnomAd4. There are 401 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.3356T>C	p.Val1119Ala	missense	Exon 19 of 21	NP_055647.2	O60343-1
	TBC1D4	NM_001286658.2		c.3332T>C	p.Val1111Ala	missense	Exon 18 of 20	NP_001273587.1	O60343-3
	TBC1D4	NM_001286659.2		c.3167T>C	p.Val1056Ala	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.3356T>C	p.Val1119Ala	missense	Exon 19 of 21	ENSP00000366863.3	O60343-1
	TBC1D4	ENST00000431480.6	TSL:1	c.3332T>C	p.Val1111Ala	missense	Exon 18 of 20	ENSP00000395986.2	O60343-3
	TBC1D4	ENST00000377625.6	TSL:1	c.3167T>C	p.Val1056Ala	missense	Exon 17 of 19	ENSP00000366852.2	O60343-2

Frequencies

GnomAD3 genomes AF: 0.00536 AC: 816 AN: 152180 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00137 AC: 340 AN: 248706 AF XY: 0.00102

Gnomad AFR exome AF: 0.0194

Gnomad AMR exome AF: 0.000902

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000996

GnomAD4 exome AF: 0.000504 AC: 736 AN: 1460880 Hom.: 3 Cov.: 30 AF XY: 0.000425 AC XY: 309 AN XY: 726776

African (AFR) AF: 0.0175 AC: 584 AN: 33422

American (AMR) AF: 0.00121 AC: 54 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.00 AC: 0 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53232

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5750

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111538

Other (OTH) AF: 0.00123 AC: 74 AN: 60350

GnomAD4 genome AF: 0.00538 AC: 819 AN: 152298 Hom.: 7 Cov.: 32 AF XY: 0.00539 AC XY: 401 AN XY: 74466

African (AFR) AF: 0.0186 AC: 775 AN: 41570

American (AMR) AF: 0.00235 AC: 36 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00129 Hom.: 4

Bravo AF: 0.00611

ESP6500AA AF: 0.0159 AC: 58

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00164 AC: 198

Asia WGS AF: 0.000578 AC: 3 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	TBC1D4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.76
MVP		0.83
MPC		1.2
ClinPred		0.029	T
GERP RS		5.4
Varity_R		0.55
gMVP		0.60
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs58232698; hg19: chr13-75866368;