rs76851570

chr13-75288980-T-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.3617A>G(p.Asn1206Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 1,613,960 control chromosomes in the GnomAD database, including 251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (15 hom., cov: 32)
  • Exomes 𝑓: 0.016 (236 hom.)
• Consequence: TBC1D4 NM_014832.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.61

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=0.0054231584).
• BP6: Variant 13-75288980-T-C is Benign according to our data. Variant chr13-75288980-T-C is described in ClinVar as [Benign]. Clinvar id is 130553.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-75288980-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0103 (1565/152314) while in subpopulation SAS AF= 0.0317 (153/4834). AF 95% confidence interval is 0.0276. There are 15 homozygotes in gnomad4. There are 748 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D4	NM_014832.5	c.3617A>G	p.Asn1206Ser	missense_variant	20/21	ENST00000377636.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D4	ENST00000377636.8	c.3617A>G	p.Asn1206Ser	missense_variant	20/21	2	NM_014832.5	A1
TBC1D4	ENST00000431480.6	c.3593A>G	p.Asn1198Ser	missense_variant	19/20	1		P3
TBC1D4	ENST00000377625.6	c.3428A>G	p.Asn1143Ser	missense_variant	18/19	1		A1
TBC1D4	ENST00000648194.1	c.2885A>G	p.Asn962Ser	missense_variant	19/20

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1566 AN: 152196 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0314

Gnomad FIN AF: 0.00706

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0134 AC: 3348 AN: 249288 Hom.: 39 AF XY: 0.0154 AC XY: 2078 AN XY: 135240

Gnomad AFR exome AF: 0.00310

Gnomad AMR exome AF: 0.00476

Gnomad ASJ exome AF: 0.0260

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0320

Gnomad FIN exome AF: 0.00561

Gnomad NFE exome AF: 0.0148

Gnomad OTH exome AF: 0.0164

GnomAD4 exome AF: 0.0156 AC: 22859 AN: 1461646 Hom.: 236 Cov.: 32 AF XY: 0.0163 AC XY: 11841 AN XY: 727110

Gnomad4 AFR exome AF: 0.00254

Gnomad4 AMR exome AF: 0.00528

Gnomad4 ASJ exome AF: 0.0250

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0323

Gnomad4 FIN exome AF: 0.00580

Gnomad4 NFE exome AF: 0.0159

Gnomad4 OTH exome AF: 0.0165

GnomAD4 genome AF: 0.0103 AC: 1565 AN: 152314 Hom.: 15 Cov.: 32 AF XY: 0.0100 AC XY: 748 AN XY: 74482

Gnomad4 AFR AF: 0.00267

Gnomad4 AMR AF: 0.00674

Gnomad4 ASJ AF: 0.0277

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0317

Gnomad4 FIN AF: 0.00706

Gnomad4 NFE AF: 0.0147

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0152 Hom.: 23

Bravo AF: 0.0100

TwinsUK AF: 0.0124 AC: 46

ALSPAC AF: 0.0176 AC: 68

ESP6500AA AF: 0.00324 AC: 12

ESP6500EA AF: 0.0160 AC: 131

ExAC AF: 0.0137 AC: 1652

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.0170

EpiControl AF: 0.0159

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 05, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
MetaRNN	Benign	0.0054	T;T;T;T
MetaSVM	Uncertain	0.15	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.44	T
Polyphen		1.0, 1.0, 1.0	.;D;D;D
Vest4		0.41, 0.53, 0.24
MPC		0.97
ClinPred		0.0094	T
GERP RS		5.3
Varity_R		0.44
gMVP		0.48

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: rs76851570; hg19: chr13-75863116;