4-37902468-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001396959.1(TBC1D1):c.373C>T(p.Arg125Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0922 in 1,612,780 control chromosomes in the GnomAD database, including 7,332 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.079 ( 590 hom., cov: 32)

Exomes 𝑓: 0.094 ( 6742 hom. )

Consequence

TBC1D1
NM_001396959.1 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.45

Publications

50 publications found

Variant links:

Genes affected

TBC1D1 (HGNC:11578): (TBC1 domain family member 1) TBC1D1 is the founding member of a family of proteins sharing a 180- to 200-amino acid TBC domain presumed to have a role in regulating cell growth and differentiation. These proteins share significant homology with TRE2 (USP6; MIM 604334), yeast Bub2, and CDC16 (MIM 603461) (White et al., 2000 [PubMed 10965142]).[supplied by OMIM, Mar 2008]

TBC1D1 Gene-Disease associations (from GenCC):

congenital anomaly of kidney and urinary tract
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

TBC1D1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016258061).

BP6

Variant 4-37902468-C-T is Benign according to our data. Variant chr4-37902468-C-T is described in ClinVar as [Benign]. Clinvar id is 3058918.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D1	NM_001396959.1 link	c.373C>T	p.Arg125Trp	missense_variant	Exon 2 of 22	ENST00000698857.1	NP_001383888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TBC1D1	ENST00000698857.1 link	c.373C>T	p.Arg125Trp	missense_variant	Exon 2 of 22		NM_001396959.1	ENSP00000513987.1	A0A8V8TNS9
TBC1D1	ENST00000261439.9 link	c.373C>T	p.Arg125Trp	missense_variant	Exon 2 of 20	1		ENSP00000261439.4	Q86TI0-1
TBC1D1	ENST00000508802.5 link	c.373C>T	p.Arg125Trp	missense_variant	Exon 2 of 21	2		ENSP00000423651.1	Q86TI0-2
TBC1D1	ENST00000402522.1 link	c.373C>T	p.Arg125Trp	missense_variant	Exon 2 of 3	2		ENSP00000383994.1	B5MCJ2

Frequencies

GnomAD3 genomes

AF:

0.0792

AC:

12038

AN:

151964

Hom.:

592

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0292

Gnomad AMI

AF:

0.168

Gnomad AMR

AF:

0.0694

Gnomad ASJ

AF:

0.132

Gnomad EAS

AF:

0.115

Gnomad SAS

AF:

0.132

Gnomad FIN

AF:

0.151

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.0898

Gnomad OTH

AF:

0.0939

GnomAD2 exomes

AF:

0.0972

AC:

24354

AN:

250464

AF XY:

0.0997

show subpopulations

Gnomad AFR exome

AF:

0.0267

Gnomad AMR exome

AF:

0.0770

Gnomad ASJ exome

AF:

0.139

Gnomad EAS exome

AF:

0.123

Gnomad FIN exome

AF:

0.141

Gnomad NFE exome

AF:

0.0904

Gnomad OTH exome

AF:

0.0910

GnomAD4 exome

AF:

0.0936

AC:

136736

AN:

1460698

Hom.:

6742

Cov.:

AF XY:

0.0945

AC XY:

68670

AN XY:

726650

show subpopulations

African (AFR)

AF:

0.0263

AC:

880

AN:

33472

American (AMR)

AF:

0.0770

AC:

3439

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.139

AC:

3631

AN:

26056

East Asian (EAS)

AF:

0.104

AC:

4140

AN:

39698

South Asian (SAS)

AF:

0.123

AC:

10581

AN:

86118

European-Finnish (FIN)

AF:

0.132

AC:

7057

AN:

53338

Middle Eastern (MID)

AF:

0.0763

AC:

440

AN:

5766

European-Non Finnish (NFE)

AF:

0.0907

AC:

100842

AN:

1111246

Other (OTH)

AF:

0.0949

AC:

5726

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

6065

12130

18195

24260

30325

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0791

AC:

12029

AN:

152082

Hom.:

590

Cov.:

AF XY:

0.0822

AC XY:

6111

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.0291

AC:

1207

AN:

41516

American (AMR)

AF:

0.0694

AC:

1061

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.132

AC:

459

AN:

3468

East Asian (EAS)

AF:

0.116

AC:

597

AN:

5160

South Asian (SAS)

AF:

0.131

AC:

630

AN:

4822

European-Finnish (FIN)

AF:

0.151

AC:

1594

AN:

10538

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0898

AC:

6102

AN:

67982

Other (OTH)

AF:

0.0929

AC:

196

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

583

1167

1750

2334

2917

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0879

Hom.:

2620

Bravo

AF:

0.0719

TwinsUK

AF:

0.0895

AC:

332

ALSPAC

AF:

0.0802

AC:

309

ESP6500AA

AF:

0.0295

AC:

130

ESP6500EA

AF:

0.0966

AC:

831

ExAC

AF:

0.0939

AC:

11394

Asia WGS

AF:

0.109

AC:

379

AN:

3478

EpiCase

AF:

0.0908

EpiControl

AF:

0.0940

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TBC1D1-related disorder

Benign:1

Sep 17, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.085

.;T;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.22

LIST_S2

Uncertain

0.96

D;D;D

MetaRNN

Benign

0.0016

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.69

N;N;.

PhyloP100

1.5

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.4

N;N;D

REVEL

Benign

0.13

Sift

Uncertain

0.015

D;D;D

Sift4G

Uncertain

0.017

D;D;D

Polyphen

0.96

.;D;.

Vest4

0.21

MPC

1.0

ClinPred

0.019

GERP RS

3.1

Varity_R

0.059

gMVP

0.31

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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4-37902468-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over