chr13-75286993-T-A

Position:

• chr13-75286993-T-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_014832.5(TBC1D4):​c.3696A>T​(p.Ser1232Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000327 in 1,613,670 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (1 hom.)
• Consequence: TBC1D4 NM_014832.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.913

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 13-75286993-T-A is Benign according to our data. Variant chr13-75286993-T-A is described in ClinVar as [Benign]. Clinvar id is 775344.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.913 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D4	NM_014832.5	c.3696A>T	p.Ser1232Ser	synonymous_variant	21/21	ENST00000377636.8	NP_055647.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBC1D4	ENST00000377636.8	c.3696A>T	p.Ser1232Ser	synonymous_variant	21/21	2	NM_014832.5	ENSP00000366863.3
TBC1D4	ENST00000431480.6	c.3672A>T	p.Ser1224Ser	synonymous_variant	20/20	1		ENSP00000395986.2
TBC1D4	ENST00000377625.6	c.3507A>T	p.Ser1169Ser	synonymous_variant	19/19	1		ENSP00000366852.2
TBC1D4	ENST00000648194.1	c.2964A>T	p.Ser988Ser	synonymous_variant	20/20			ENSP00000496983.1

Frequencies

GnomAD3 genomes AF: 0.000606 AC: 92 AN: 151824 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000851

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000497 AC: 123 AN: 247414 Hom.: 0 AF XY: 0.000483 AC XY: 65 AN XY: 134444

Gnomad AFR exome AF: 0.000775

Gnomad AMR exome AF: 0.000900

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000422

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000298 AC: 436 AN: 1461730 Hom.: 1 Cov.: 32 AF XY: 0.000275 AC XY: 200 AN XY: 727160

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.000918

Gnomad4 ASJ exome AF: 0.00306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000199

Gnomad4 OTH exome AF: 0.000845

GnomAD4 genome AF: 0.000606 AC: 92 AN: 151940 Hom.: 0 Cov.: 32 AF XY: 0.000525 AC XY: 39 AN XY: 74276

Gnomad4 AFR AF: 0.000849

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000580 Hom.: 0

Bravo AF: 0.000688

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 22, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.0
DANN	Benign	0.72

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: rs200847492; hg19: chr13-75861129;