Variant 3-161503679-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001080440.1(OTOL1):c.1171T>C(p.Ser391Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,461,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

OTOL1
NM_001080440.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.145

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOL1	NM_001080440.1 linkuse as main transcript	c.1171T>C	p.Ser391Pro	missense_variant	4/4	ENST00000327928.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOL1	ENST00000327928.4 linkuse as main transcript	c.1171T>C	p.Ser391Pro	missense_variant	4/4	2	NM_001080440.1	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1461490

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727002

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

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

Jun 29, 2022

The c.1171T>C (p.S391P) alteration is located in exon 4 (coding exon 4) of the OTOL1 gene. This alteration results from a T to C substitution at nucleotide position 1171, causing the serine (S) at amino acid position 391 to be replaced by a proline (P). 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

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.33

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.29

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.27

MutationAssessor

Pathogenic

3.4

MutationTaster

Benign

0.64

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.59

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.75

MutPred

0.76

Loss of MoRF binding (P = 0.0945);

MVP

0.33

MPC

0.19

ClinPred

0.96

GERP RS

2.9

Varity_R

0.89

gMVP

0.89

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