Genetic Variant NM_001396959.1:c.683T>A (chr4-38014774-T-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001396959.1(TBC1D1):c.683T>A(p.Val228Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,403,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TBC1D1
NM_001396959.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.41

Publications

0 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):

non-syndromic renal or urinary tract malformation
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.039616525).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001396959.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBC1D1	NM_001396959.1	MANE Select	c.683T>A	p.Val228Glu	missense	Exon 3 of 22	NP_001383888.1	A0A8V8TNS9
TBC1D1	NM_015173.4		c.683T>A	p.Val228Glu	missense	Exon 3 of 20	NP_055988.2
TBC1D1	NM_001253912.2		c.683T>A	p.Val228Glu	missense	Exon 3 of 21	NP_001240841.1	Q86TI0-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBC1D1	ENST00000698857.1	MANE Select	c.683T>A	p.Val228Glu	missense	Exon 3 of 22	ENSP00000513987.1	A0A8V8TNS9
TBC1D1	ENST00000261439.9	TSL:1	c.683T>A	p.Val228Glu	missense	Exon 3 of 20	ENSP00000261439.4	Q86TI0-1
TBC1D1	ENST00000961338.1		c.683T>A	p.Val228Glu	missense	Exon 3 of 23	ENSP00000631397.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1403276

Hom.:

Cov.:

AF XY:

0.00000287

AC XY:

AN XY:

697038

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32616

American (AMR)

AF:

0.00

AC:

AN:

43014

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24224

East Asian (EAS)

AF:

0.00

AC:

AN:

38228

South Asian (SAS)

AF:

0.0000233

AC:

AN:

85752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46654

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5430

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1070628

Other (OTH)

AF:

0.00

AC:

AN:

56730

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

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

2.4

(source)

DANN

Benign

0.19

DEOGEN2

Benign

0.018

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.080

M_CAP

Benign

0.0026

MetaRNN

Benign

0.040

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

PhyloP100

1.4

PrimateAI

Benign

0.43

PROVEAN

Benign

0.99

REVEL

Benign

0.031

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.056

MutPred

0.19

Gain of solvent accessibility (P = 0.0039)

MVP

0.18

MPC

0.85

ClinPred

0.016

GERP RS

0.31

Varity_R

0.044

gMVP

0.34

Mutation Taster

=99/1

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over