13-75288980-T-C

Variant names:

• chr13-75288980-T-C
• rs76851570
• NM_014832.5:c.3617A>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.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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.61
• Publications: 15 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=0.0054231584).
• BP6: Variant 13-75288980-T-C is Benign according to our data. Variant chr13-75288980-T-C is described in ClinVar as Benign. ClinVar VariationId is 130553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D4	NM_014832.5	MANE Select	c.3617A>G	p.Asn1206Ser	missense	Exon 20 of 21	NP_055647.2
	TBC1D4	NM_001286658.2		c.3593A>G	p.Asn1198Ser	missense	Exon 19 of 20	NP_001273587.1
	TBC1D4	NM_001286659.2		c.3428A>G	p.Asn1143Ser	missense	Exon 18 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.3617A>G	p.Asn1206Ser	missense	Exon 20 of 21	ENSP00000366863.3
	TBC1D4	ENST00000431480.6	TSL:1	c.3593A>G	p.Asn1198Ser	missense	Exon 19 of 20	ENSP00000395986.2
	TBC1D4	ENST00000377625.6	TSL:1	c.3428A>G	p.Asn1143Ser	missense	Exon 18 of 19	ENSP00000366852.2

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

GnomAD2 exomes AF: 0.0134 AC: 3348 AN: 249288 AF XY: 0.0154

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 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

African (AFR) AF: 0.00254 AC: 85 AN: 33462

American (AMR) AF: 0.00528 AC: 236 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0250 AC: 653 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.0323 AC: 2786 AN: 86254

European-Finnish (FIN) AF: 0.00580 AC: 310 AN: 53406

Middle Eastern (MID) AF: 0.0206 AC: 119 AN: 5768

European-Non Finnish (NFE) AF: 0.0159 AC: 17671 AN: 1111862

Other (OTH) AF: 0.0165 AC: 998 AN: 60384

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

African (AFR) AF: 0.00267 AC: 111 AN: 41566

American (AMR) AF: 0.00674 AC: 103 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 96 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0317 AC: 153 AN: 4834

European-Finnish (FIN) AF: 0.00706 AC: 75 AN: 10628

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0147 AC: 998 AN: 68024

Other (OTH) AF: 0.0123 AC: 26 AN: 2112

Alfa AF: 0.0142 Hom.: 35

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Sep 05, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0054	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.6
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.41
MPC		0.97
ClinPred		0.0094	T
GERP RS		5.3
Varity_R		0.44
gMVP		0.48
Mutation Taster		=82/18	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: rs76851570; hg19: chr13-75863116; COSMIC: COSV107499448;