Genetic Variant TOGARAM1:p.Thr105Asn (chr14-44962735-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001308120.2(TOGARAM1):c.314C>A(p.Thr105Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,613,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

TOGARAM1
NM_001308120.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.29

Publications

2 publications found

Variant links:

Genes affected

TOGARAM1 (HGNC:19959): (TOG array regulator of axonemal microtubules 1) Predicted to enable microtubule binding activity. Predicted to be involved in organelle assembly and positive regulation of microtubule polymerization. Predicted to be located in ciliary basal body. Predicted to be active in cilium and microtubule cytoskeleton. Predicted to colocalize with microtubule. Implicated in Joubert syndrome. [provided by Alliance of Genome Resources, Apr 2022]

TOGARAM1 links:

KLHL28 (HGNC:19741): (kelch like family member 28)

KLHL28 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1373361).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308120.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TOGARAM1	NM_001308120.2	MANE Select	c.314C>A	p.Thr105Asn	missense	Exon 1 of 20	NP_001295049.1	G3XAE9
TOGARAM1	NM_015091.4		c.314C>A	p.Thr105Asn	missense	Exon 1 of 19	NP_055906.2	Q9Y4F4-1
TOGARAM1	NR_131765.2		n.546C>A		non_coding_transcript_exon	Exon 1 of 20

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TOGARAM1	ENST00000361462.7	TSL:1 MANE Select	c.314C>A	p.Thr105Asn	missense	Exon 1 of 20	ENSP00000354917.2	G3XAE9
TOGARAM1	ENST00000361577.7	TSL:1	c.314C>A	p.Thr105Asn	missense	Exon 1 of 19	ENSP00000355045.3	Q9Y4F4-1
TOGARAM1	ENST00000555607.1	TSL:1	n.522C>A		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152212

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000639

AC:

AN:

250368

AF XY:

0.0000443

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000527

AC:

AN:

1461578

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000157

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000620

AC:

AN:

1112012

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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

AF:

0.0000328

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.012

Eigen

Benign

-0.075

Eigen_PC

Benign

-0.069

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.84

M_CAP

Benign

0.0069

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.96

PhyloP100

3.3

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.93

REVEL

Benign

0.092

Sift

Uncertain

0.0030

Sift4G

Pathogenic

0.0

Polyphen

0.62

Vest4

0.14

MutPred

0.073

Loss of phosphorylation at T105 (P = 0.0413)

MVP

0.37

MPC

0.34

ClinPred

0.54

GERP RS

4.9

Varity_R

0.25

gMVP

0.34

Mutation Taster

=87/13

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over