Variant 3-161503229-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001080440.1(OTOL1):c.721A>G(p.Lys241Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000164 in 1,247,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000038 ( 0 hom., cov: 21)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

OTOL1
NM_001080440.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.71

Variant links:

Genes affected

OTOL1 (HGNC:34071): (otolin 1) This gene encodes a secreted glycoprotein with a C-terminal complement Cq1-like globular domain that belongs to the C1q/tumor necrosis factor-related protein (CTRP) family. The encoded protein is expressed in the inner ear and forms a multimeric complex called the otoconia, together with cerebellin-1 and otoconin-90, as part of the otoconial membrane. It contains extensive posttranslational modifications including hydroxylated prolines and glycosylated lysines. Naturally occurring mutations in this gene are associated with abnormal otoconia formation and balance deficits resulting from vestibular dysfunction. [provided by RefSeq, Jul 2017]

OTOL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23564214).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOL1	NM_001080440.1 linkuse as main transcript	c.721A>G	p.Lys241Glu	missense_variant	4/4	ENST00000327928.4	NP_001073909.1	A6NHN0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOL1	ENST00000327928.4 linkuse as main transcript	c.721A>G	p.Lys241Glu	missense_variant	4/4	2	NM_001080440.1	ENSP00000330808.4		A6NHN0

Frequencies

GnomAD3 genomes

AF:

0.0000381

AC:

AN:

131402

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000286

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:

0.0000638

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000376

AC:

AN:

79724

Hom.:

AF XY:

0.0000762

AC XY:

AN XY:

39380

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000960

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000179

AC:

200

AN:

1115910

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

AN XY:

538810

show subpopulations

Gnomad4 AFR exome

AF:

0.0000444

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000205

Gnomad4 OTH exome

AF:

0.000291

GnomAD4 genome

AF:

0.0000380

AC:

AN:

131472

Hom.:

Cov.:

AF XY:

0.0000158

AC XY:

AN XY:

63260

show subpopulations

Gnomad4 AFR

AF:

0.0000286

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000637

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000103

Hom.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2021

The c.721A>G (p.K241E) alteration is located in exon 4 (coding exon 4) of the OTOL1 gene. This alteration results from a A to G substitution at nucleotide position 721, causing the lysine (K) at amino acid position 241 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0054

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.23

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

M_CAP

Benign

0.066

MetaRNN

Benign

0.24

MetaSVM

Uncertain

-0.10

MutationAssessor

Benign

1.8

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.46

Sift

Benign

0.067

Sift4G

Benign

0.18

Polyphen

0.89

Vest4

0.46

MVP

0.30

MPC

0.024

ClinPred

0.43

GERP RS

2.9

Varity_R

0.19

gMVP

0.25

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over