13-75324385-G-C

Variant names:

• chr13-75324385-G-C
• rs61736969
• NM_014832.5:c.2050C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 14/21 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, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.40
• Publications: 43 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=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 VariationId is 130546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D4	NM_014832.5	MANE Select	c.2050C>G	p.Arg684Gly	missense	Exon 11 of 21	NP_055647.2	O60343-1
	TBC1D4	NM_001286658.2		c.2050C>G	p.Arg684Gly	missense	Exon 11 of 20	NP_001273587.1	O60343-3
	TBC1D4	NM_001286659.2		c.2033+1812C>G		intron	N/A	NP_001273588.1	O60343-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D4	ENST00000377636.8	TSL:2 MANE Select	c.2050C>G	p.Arg684Gly	missense	Exon 11 of 21	ENSP00000366863.3	O60343-1
	TBC1D4	ENST00000431480.6	TSL:1	c.2050C>G	p.Arg684Gly	missense	Exon 11 of 20	ENSP00000395986.2	O60343-3
	TBC1D4	ENST00000377625.6	TSL:1	c.2033+1812C>G		intron	N/A	ENSP00000366852.2	O60343-2

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

GnomAD2 exomes AF: 0.00188 AC: 468 AN: 249464 AF XY: 0.00149

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 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

African (AFR) AF: 0.0272 AC: 909 AN: 33472

American (AMR) AF: 0.000827 AC: 37 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111862

Other (OTH) AF: 0.00116 AC: 70 AN: 60380

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

African (AFR) AF: 0.0253 AC: 1051 AN: 41514

American (AMR) AF: 0.00170 AC: 26 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68000

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.14	N
PhyloP100		2.4
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.083
Sift	Benign	0.060	T
Sift4G	Benign	0.40	T
Polyphen		0.0010	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
Mutation Taster		=276/24	polymorphism

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

Other links and lift over

dbSNP: rs61736969; hg19: chr13-75898521;