13-75286862-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_014832.5(TBC1D4):c.3827A>G(p.Asn1276Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000867 in 1,613,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: TBC1D4 NM_014832.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.752

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.015047044).
• BP6: Variant 13-75286862-T-C is Benign according to our data. Variant chr13-75286862-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 436949.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D4	NM_014832.5	c.3827A>G	p.Asn1276Ser	missense_variant	21/21	ENST00000377636.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D4	ENST00000377636.8	c.3827A>G	p.Asn1276Ser	missense_variant	21/21	2	NM_014832.5	A1
TBC1D4	ENST00000431480.6	c.3803A>G	p.Asn1268Ser	missense_variant	20/20	1		P3
TBC1D4	ENST00000377625.6	c.3638A>G	p.Asn1213Ser	missense_variant	19/19	1		A1
TBC1D4	ENST00000648194.1	c.3095A>G	p.Asn1032Ser	missense_variant	20/20

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000923 AC: 23 AN: 249196 Hom.: 0 AF XY: 0.0000962 AC XY: 13 AN XY: 135204

Gnomad AFR exome AF: 0.00116

Gnomad AMR exome AF: 0.0000582

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: 0.00000884

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000417 AC: 61 AN: 1461692 Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30 AN XY: 727136

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74478

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.000555

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000124 AC: 15

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 05, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.27
Dann	Benign	0.71
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.015	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
Polyphen		0.0050, 0.0	.;B;B;B
Vest4		0.021, 0.024, 0.029
MVP		0.40
MPC		0.27
ClinPred		0.0060	T
GERP RS		-2.4
Varity_R		0.021
gMVP		0.24

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: rs199954281; hg19: chr13-75860998;