rs56223054

chr13-75326374-G-Achr13-75326374-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014832.5(TBC1D4):c.1856C>T(p.Pro619Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00453 in 1,614,104 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (15 hom.)
• Consequence: TBC1D4 NM_014832.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.96

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004371673).
• BP6: Variant 13-75326374-G-A is Benign according to our data. Variant chr13-75326374-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 436950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-75326374-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D4	NM_014832.5	c.1856C>T	p.Pro619Leu	missense_variant	10/21	ENST00000377636.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D4	ENST00000377636.8	c.1856C>T	p.Pro619Leu	missense_variant	10/21	2	NM_014832.5	A1

Frequencies

GnomAD3 genomes AF: 0.00336 AC: 511 AN: 152098 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00540

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00325 AC: 807 AN: 248676 Hom.: 3 AF XY: 0.00343 AC XY: 463 AN XY: 134960

Gnomad AFR exome AF: 0.000581

Gnomad AMR exome AF: 0.00290

Gnomad ASJ exome AF: 0.00447

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.000649

Gnomad NFE exome AF: 0.00500

Gnomad OTH exome AF: 0.00512

GnomAD4 exome AF: 0.00465 AC: 6804 AN: 1461888 Hom.: 15 Cov.: 31 AF XY: 0.00460 AC XY: 3348 AN XY: 727242

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00306

Gnomad4 ASJ exome AF: 0.00448

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00130

Gnomad4 FIN exome AF: 0.000842

Gnomad4 NFE exome AF: 0.00552

Gnomad4 OTH exome AF: 0.00369

GnomAD4 genome AF: 0.00336 AC: 511 AN: 152216 Hom.: 1 Cov.: 32 AF XY: 0.00290 AC XY: 216 AN XY: 74418

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00540

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00399 Hom.: 2

Bravo AF: 0.00339

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000742 AC: 3

ESP6500EA AF: 0.00647 AC: 54

ExAC AF: 0.00332 AC: 402

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.00463

EpiControl AF: 0.00522

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 14, 2017

- -

TBC1D4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 02, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	16
Dann	Benign	0.97
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.32	T;T;T;T;T
MetaRNN	Benign	0.0044	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.51	D;D;N;N
PrimateAI	Uncertain	0.52	T
Polyphen		0.0	.;B;B;B;.
Vest4		0.19, 0.11, 0.13
MVP		0.45
MPC		0.34
ClinPred		0.010	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.043
gMVP		0.13

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: rs56223054; hg19: chr13-75900510; COSMIC: COSV100884917; COSMIC: COSV100884917;