13-75324385-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014832.5(TBC1D4):c.2050C>G(p.Arg684Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,613,834 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0072 (20 hom., cov: 33)
  • Exomes 𝑓: 0.00071 (10 hom.)
• Consequence: TBC1D4 NM_014832.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.40

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=0.0054097176).
• BP6: Variant 13-75324385-G-C is Benign according to our data. Variant chr13-75324385-G-C is described in ClinVar as [Benign]. Clinvar id is 130546.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00719 (1094/152176) while in subpopulation AFR AF= 0.0253 (1051/41514). AF 95% confidence interval is 0.024. There are 20 homozygotes in gnomad4. There are 551 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D4	NM_014832.5	c.2050C>G	p.Arg684Gly	missense_variant	11/21	ENST00000377636.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D4	ENST00000377636.8	c.2050C>G	p.Arg684Gly	missense_variant	11/21	2	NM_014832.5	A1

Frequencies

GnomAD3 genomes AF: 0.00719 AC: 1093 AN: 152058 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.0254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

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: 0.0000294

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00188 AC: 468 AN: 249464 Hom.: 9 AF XY: 0.00149 AC XY: 202 AN XY: 135342

Gnomad AFR exome AF: 0.0281

Gnomad AMR exome AF: 0.000753

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000707 AC: 1033 AN: 1461658 Hom.: 10 Cov.: 31 AF XY: 0.000598 AC XY: 435 AN XY: 727126

Gnomad4 AFR exome AF: 0.0272

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.00719 AC: 1094 AN: 152176 Hom.: 20 Cov.: 33 AF XY: 0.00741 AC XY: 551 AN XY: 74400

Gnomad4 AFR AF: 0.0253

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.00825

ESP6500AA AF: 0.0256 AC: 96

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00223 AC: 269

EpiCase AF: 0.00

EpiControl AF: 0.000119

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

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0054	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.14	N;N
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.70	N;N
REVEL	Benign	0.083
Sift	Benign	0.060	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.0010	B;B
Vest4		0.40
MVP		0.54
MPC		0.43
ClinPred		0.010	T
GERP RS		4.6
Varity_R		0.17
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs61736969; hg19: chr13-75898521;