13-75310080-C-T

Variant names:

• chr13-75310080-C-T
• rs1062087
• NM_014832.5:c.2455G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0320
• Publications: 37 publications found

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

Our verdict: Benign. The variant received -20 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 VariationId is 130549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.906 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014832.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D4	NM_014832.5	MANE Select	c.2455G>A	p.Val819Ile	missense	Exon 14 of 21	NP_055647.2
	TBC1D4	NM_001286658.2		c.2431G>A	p.Val811Ile	missense	Exon 13 of 20	NP_001273587.1
	TBC1D4	NM_001286659.2		c.2266G>A	p.Val756Ile	missense	Exon 12 of 19	NP_001273588.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D4	ENST00000377636.8	TSL:2 MANE Select	c.2455G>A	p.Val819Ile	missense	Exon 14 of 21	ENSP00000366863.3
	TBC1D4	ENST00000431480.6	TSL:1	c.2431G>A	p.Val811Ile	missense	Exon 13 of 20	ENSP00000395986.2
	TBC1D4	ENST00000377625.6	TSL:1	c.2266G>A	p.Val756Ile	missense	Exon 12 of 19	ENSP00000366852.2

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

GnomAD2 exomes AF: 0.825 AC: 205472 AN: 249084 AF XY: 0.841

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 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

African (AFR) AF: 0.468 AC: 15661 AN: 33478

American (AMR) AF: 0.691 AC: 30907 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.872 AC: 22792 AN: 26136

East Asian (EAS) AF: 0.779 AC: 30912 AN: 39700

South Asian (SAS) AF: 0.933 AC: 80434 AN: 86252

European-Finnish (FIN) AF: 0.822 AC: 43894 AN: 53402

Middle Eastern (MID) AF: 0.877 AC: 5056 AN: 5766

European-Non Finnish (NFE) AF: 0.885 AC: 984374 AN: 1111940

Other (OTH) AF: 0.845 AC: 51050 AN: 60390

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

African (AFR) AF: 0.485 AC: 20085 AN: 41410

American (AMR) AF: 0.717 AC: 10954 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.859 AC: 2981 AN: 3472

East Asian (EAS) AF: 0.809 AC: 4175 AN: 5158

South Asian (SAS) AF: 0.928 AC: 4460 AN: 4804

European-Finnish (FIN) AF: 0.831 AC: 8801 AN: 10596

Middle Eastern (MID) AF: 0.833 AC: 245 AN: 294

European-Non Finnish (NFE) AF: 0.888 AC: 60366 AN: 68010

Other (OTH) AF: 0.766 AC: 1619 AN: 2114

Alfa AF: 0.848 Hom.: 245744

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.024	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.018	T
MetaRNN	Benign	6.3e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N
PhyloP100		0.032
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.057
Sift	Benign	0.32	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.051
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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