NM_014832.5:c.3824T>C

Variant names:

• chr13-75286865-A-G
• rs557337
• NM_014832.5:c.3824T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014832.5(TBC1D4):​c.3824T>C​(p.Val1275Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0749 in 1,613,742 control chromosomes in the GnomAD database, including 12,177 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (5386 hom., cov: 32)
  • Exomes 𝑓: 0.064 (6791 hom.)
• Consequence: TBC1D4 NM_014832.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 4.43
• Publications: 15 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.917383E-4).
• BP6: Variant 13-75286865-A-G is Benign according to our data. Variant chr13-75286865-A-G is described in ClinVar as Benign. ClinVar VariationId is 130861.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.486 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.3824T>C	p.Val1275Ala	missense	Exon 21 of 21	NP_055647.2	O60343-1
	TBC1D4	NM_001286658.2		c.3800T>C	p.Val1267Ala	missense	Exon 20 of 20	NP_001273587.1	O60343-3
	TBC1D4	NM_001286659.2		c.3635T>C	p.Val1212Ala	missense	Exon 19 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.3824T>C	p.Val1275Ala	missense	Exon 21 of 21	ENSP00000366863.3	O60343-1
	TBC1D4	ENST00000431480.6	TSL:1	c.3800T>C	p.Val1267Ala	missense	Exon 20 of 20	ENSP00000395986.2	O60343-3
	TBC1D4	ENST00000377625.6	TSL:1	c.3635T>C	p.Val1212Ala	missense	Exon 19 of 19	ENSP00000366852.2	O60343-2

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27099 AN: 151958 Hom.: 5365 Cov.: 32

Gnomad AFR AF: 0.492

Gnomad AMI AF: 0.0901

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.0672

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0155

Gnomad FIN AF: 0.0461

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0593

Gnomad OTH AF: 0.147

GnomAD2 exomes AF: 0.0749 AC: 18650 AN: 249138 AF XY: 0.0661

Gnomad AFR exome AF: 0.504

Gnomad AMR exome AF: 0.0545

Gnomad ASJ exome AF: 0.0646

Gnomad EAS exome AF: 0.000334

Gnomad FIN exome AF: 0.0413

Gnomad NFE exome AF: 0.0584

Gnomad OTH exome AF: 0.0636

GnomAD4 exome AF: 0.0641 AC: 93712 AN: 1461666 Hom.: 6791 Cov.: 32 AF XY: 0.0611 AC XY: 44436 AN XY: 727132

African (AFR) AF: 0.509 AC: 17026 AN: 33468

American (AMR) AF: 0.0597 AC: 2666 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.0636 AC: 1663 AN: 26136

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39696

South Asian (SAS) AF: 0.0153 AC: 1318 AN: 86256

European-Finnish (FIN) AF: 0.0435 AC: 2323 AN: 53392

Middle Eastern (MID) AF: 0.0867 AC: 500 AN: 5764

European-Non Finnish (NFE) AF: 0.0572 AC: 63576 AN: 1111938

Other (OTH) AF: 0.0767 AC: 4631 AN: 60378

GnomAD4 genome AF: 0.179 AC: 27163 AN: 152076 Hom.: 5386 Cov.: 32 AF XY: 0.173 AC XY: 12881 AN XY: 74354

African (AFR) AF: 0.492 AC: 20374 AN: 41428

American (AMR) AF: 0.101 AC: 1541 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0672 AC: 233 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.0151 AC: 73 AN: 4820

European-Finnish (FIN) AF: 0.0461 AC: 489 AN: 10598

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0593 AC: 4032 AN: 67990

Other (OTH) AF: 0.145 AC: 306 AN: 2108

Alfa AF: 0.0929 Hom.: 6550

Bravo AF: 0.194

TwinsUK AF: 0.0596 AC: 221

ALSPAC AF: 0.0550 AC: 212

ESP6500AA AF: 0.462 AC: 1770

ESP6500EA AF: 0.0586 AC: 484

ExAC AF: 0.0830 AC: 10026

Asia WGS AF: 0.0400 AC: 137 AN: 3478

EpiCase AF: 0.0592

EpiControl AF: 0.0603

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.9
DANN	Benign	0.25
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.035	T
MetaRNN	Benign	0.00049	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.90	N
PhyloP100		4.4
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.83	N
REVEL	Benign	0.087
Sift	Benign	1.0	T
Sift4G	Benign	0.90	T
Polyphen		0.0	B
Vest4		0.024
MPC		0.40
ClinPred		0.0055	T
GERP RS		3.9
Varity_R		0.012
gMVP		0.23
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs557337; hg19: chr13-75861001; COSMIC: COSV66493282;