Genetic Variant OTOG:c.94+17C>A (chr11-17547483-C-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_001277269.2(OTOG):c.111C>A(p.Asp37Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000168 in 1,192,260 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. Synonymous variant affecting the same amino acid position (i.e. D37D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000017 ( 0 hom. )

Consequence

OTOG
NM_001277269.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.483

Publications

0 publications found

Variant links:

Genes affected

OTOG (HGNC:8516): (otogelin) The protein encoded by this gene is a component of the acellular membranes of the inner ear. Disruption of the orthologous mouse gene shows that it plays a role in auditory and vestibular functions. It is involved in fibrillar network organization, the anchoring of otoconial membranes and cupulae to the neuroepithelia, and likely in sound stimulation resistance. Mutations in this gene cause autosomal recessive nonsyndromic deafness, type 18B. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

OTOG Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 18B
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

OTOG links:

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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=0.062347084).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001277269.2. 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
	OTOG	NM_001292063.2	MANE Select	c.94+17C>A		intron	N/A	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.111C>A	p.Asp37Glu	missense	Exon 1 of 55	NP_001264198.1	Q6ZRI0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.94+17C>A		intron	N/A	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.111C>A	p.Asp37Glu	missense	Exon 1 of 55	ENSP00000382323.2	Q6ZRI0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000168

AC:

AN:

1192260

Hom.:

Cov.:

AF XY:

0.00000348

AC XY:

AN XY:

575048

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

24180

American (AMR)

AF:

0.0000740

AC:

AN:

13512

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16662

East Asian (EAS)

AF:

0.00

AC:

AN:

27968

South Asian (SAS)

AF:

0.00

AC:

AN:

47958

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4888

European-Non Finnish (NFE)

AF:

0.00000102

AC:

AN:

981816

Other (OTH)

AF:

0.00

AC:

AN:

48870

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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

0.092

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.78

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.023

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.24

M_CAP

Benign

0.038

MetaRNN

Benign

0.062

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.46

PhyloP100

0.48

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.14

REVEL

Benign

0.12

Sift

Benign

0.57

Sift4G

Benign

1.0

Vest4

0.051

MutPred

0.15

Gain of methylation at R40 (P = 0.0794)

MVP

0.061

ClinPred

0.14

GERP RS

4.2

PromoterAI

0.037

Neutral

(source)

Varity_R

0.092

gMVP

0.025

Mutation Taster

=96/4

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over