dbSNP rs59426552: TBC1D1:p.Arg213His (chr4-38014729-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001396959.1(TBC1D1):c.638G>A(p.Arg213His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 806,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R213P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

TBC1D1
NM_001396959.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.615

Publications

4 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0790495).

BS2

High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D1	NM_001396959.1 link	c.638G>A	p.Arg213His	missense_variant	Exon 3 of 22	ENST00000698857.1	NP_001383888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D1	ENST00000698857.1 link	c.638G>A	p.Arg213His	missense_variant	Exon 3 of 22		NM_001396959.1	ENSP00000513987.1		A0A8V8TNS9

Frequencies

GnomAD3 genomes

AF:

0.00000717

AC:

AN:

139502

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000267

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000125

AC:

AN:

239354

AF XY:

0.0000227

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000255

AC:

AN:

666826

Hom.:

Cov.:

AF XY:

0.0000427

AC XY:

AN XY:

350926

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17642

American (AMR)

AF:

0.00

AC:

AN:

38054

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15406

East Asian (EAS)

AF:

0.00

AC:

AN:

21158

South Asian (SAS)

AF:

0.000194

AC:

AN:

72236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3654

European-Non Finnish (NFE)

AF:

0.00000461

AC:

AN:

433712

Other (OTH)

AF:

0.0000352

AC:

AN:

28370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000717

AC:

AN:

139502

Hom.:

Cov.:

AF XY:

0.0000148

AC XY:

AN XY:

67594

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

38794

American (AMR)

AF:

0.00

AC:

AN:

14196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3280

East Asian (EAS)

AF:

0.00

AC:

AN:

3926

South Asian (SAS)

AF:

0.000267

AC:

AN:

3744

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8696

Middle Eastern (MID)

AF:

0.00

AC:

AN:

306

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

63760

Other (OTH)

AF:

0.00

AC:

AN:

1954

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000252

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.071

.;T;T

Eigen

Benign

-0.89

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.75

T;T;T

M_CAP

Benign

0.0098

MetaRNN

Benign

0.079

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N;.

PhyloP100

0.61

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.0

N;N;N

REVEL

Benign

0.043

Sift

Benign

0.12

T;T;T

Sift4G

Benign

0.12

T;T;T

Polyphen

0.60

.;P;.

Vest4

0.042

MutPred

0.22

Loss of glycosylation at P216 (P = 0.0095);Loss of glycosylation at P216 (P = 0.0095);.;

MVP

0.24

MPC

0.81

ClinPred

0.16

GERP RS

-0.059

Varity_R

0.023

gMVP

0.20

Mutation Taster

=97/3

polymorphism

(source)

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

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rs59426552

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over