rs1062087

chr13-75310080-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014832.5(TBC1D4):c.2455G>A(p.Val819Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.855 in 1,613,816 control chromosomes in the GnomAD database, including 597,291 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.75 (45590 hom., cov: 31)
  • Exomes 𝑓: 0.87 (551701 hom.)
• Consequence: TBC1D4 NM_014832.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0320

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.2582626E-7).
• BP6: Variant 13-75310080-C-T is Benign according to our data. Variant chr13-75310080-C-T is described in ClinVar as [Benign]. Clinvar id is 130549.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D4	NM_014832.5	c.2455G>A	p.Val819Ile	missense_variant	14/21	ENST00000377636.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D4	ENST00000377636.8	c.2455G>A	p.Val819Ile	missense_variant	14/21	2	NM_014832.5	A1

Frequencies

GnomAD3 genomes AF: 0.754 AC: 114515 AN: 151926 Hom.: 45563 Cov.: 31

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.989

Gnomad AMR AF: 0.718

Gnomad ASJ AF: 0.859

Gnomad EAS AF: 0.809

Gnomad SAS AF: 0.928

Gnomad FIN AF: 0.831

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.888

Gnomad OTH AF: 0.763

GnomAD3 exomes AF: 0.825 AC: 205472 AN: 249084 Hom.: 86445 AF XY: 0.841 AC XY: 113604 AN XY: 135138

Gnomad AFR exome AF: 0.477

Gnomad AMR exome AF: 0.687

Gnomad ASJ exome AF: 0.871

Gnomad EAS exome AF: 0.813

Gnomad SAS exome AF: 0.934

Gnomad FIN exome AF: 0.825

Gnomad NFE exome AF: 0.882

Gnomad OTH exome AF: 0.839

GnomAD4 exome AF: 0.865 AC: 1265080 AN: 1461772 Hom.: 551701 Cov.: 62 AF XY: 0.870 AC XY: 632502 AN XY: 727190

Gnomad4 AFR exome AF: 0.468

Gnomad4 AMR exome AF: 0.691

Gnomad4 ASJ exome AF: 0.872

Gnomad4 EAS exome AF: 0.779

Gnomad4 SAS exome AF: 0.933

Gnomad4 FIN exome AF: 0.822

Gnomad4 NFE exome AF: 0.885

Gnomad4 OTH exome AF: 0.845

GnomAD4 genome AF: 0.754 AC: 114588 AN: 152044 Hom.: 45590 Cov.: 31 AF XY: 0.753 AC XY: 56006 AN XY: 74348

Gnomad4 AFR AF: 0.485

Gnomad4 AMR AF: 0.717

Gnomad4 ASJ AF: 0.859

Gnomad4 EAS AF: 0.809

Gnomad4 SAS AF: 0.928

Gnomad4 FIN AF: 0.831

Gnomad4 NFE AF: 0.888

Gnomad4 OTH AF: 0.766

Alfa AF: 0.863 Hom.: 139234

Bravo AF: 0.732

TwinsUK AF: 0.890 AC: 3299

ALSPAC AF: 0.891 AC: 3433

ESP6500AA AF: 0.504 AC: 1880

ESP6500EA AF: 0.884 AC: 7236

ExAC AF: 0.825 AC: 99680

Asia WGS AF: 0.835 AC: 2904 AN: 3478

EpiCase AF: 0.887

EpiControl AF: 0.882

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	5.4
Dann	Benign	0.76
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.018	T;T;T;T;T
MetaRNN	Benign	6.3e-7	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.39	T
Polyphen		0.0	.;B;B;B;.
Vest4		0.051, 0.024, 0.0090
MPC		0.27
ClinPred		0.0027	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.011
gMVP		0.034

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: rs1062087; hg19: chr13-75884216; COSMIC: COSV66492143; COSMIC: COSV66492143;