Genetic Variant OTOP1:p.Ala601Thr (chr4-4188841-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_177998.3(OTOP1):c.1801G>A(p.Ala601Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000285 in 1,613,676 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

OTOP1
NM_177998.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.16

Publications

1 publications found

Variant links:

Genes affected

OTOP1 (HGNC:19656): (otopetrin 1) This gene encodes a transmembrane protein which belongs to the otopetrin domain protein family and is required for the formation of otoconia and otoliths, calcium carbonate biominerals within the inner ear of mammals that are required for the detection of linear acceleration and gravity. This gene modulates purinergic control of intracellular calcium in vestibular supporting cells. Naturally occurring mutations in the orthologous mouse gene are associated with nonsyndromic otoconia agenesis and a consequent balance defect. The orthologous mouse gene is also induced in white adipose tissue during obesity. The encoded protein is a component of a counterinflammatory pathway that attenuates obesity-induced adipose tissue inflammation and plays an adaptive role in maintaining metabolic homeostasis in obesity. [provided by RefSeq, Jul 2017]

OTOP1 links:

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ACMG classification

Classification was made for transcript

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177998.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOP1	NM_177998.3	MANE Select	c.1801G>A	p.Ala601Thr	missense	Exon 6 of 6	NP_819056.1	Q7RTM1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOP1	ENST00000296358.5	TSL:1 MANE Select	c.1801G>A	p.Ala601Thr	missense	Exon 6 of 6	ENSP00000296358.4	Q7RTM1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000399

AC:

AN:

250684

AF XY:

0.0000590

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461510

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727060

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33472

American (AMR)

AF:

0.0000671

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.000227

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000135

AC:

AN:

1111754

Other (OTH)

AF:

0.0000331

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.0000591

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41446

American (AMR)

AF:

0.0000655

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.000192

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

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:

0.0000434

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.010

MetaRNN

Uncertain

0.72

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

PhyloP100

4.2

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.6

REVEL

Benign

0.18

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.031

Polyphen

0.99

Vest4

0.66

MutPred

0.74

Loss of methylation at R598 (P = 0.0677)

MVP

0.34

MPC

0.13

ClinPred

0.23

GERP RS

2.6

Varity_R

0.58

gMVP

0.85

Mutation Taster

=80/20

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over