Genetic Variant OTOG:p.Pro1228Arg (chr11-17599671-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001292063.2(OTOG):c.3683C>G(p.Pro1228Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000143 in 1,398,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1228L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 missense, splice_region

Scores

Splicing: ADA: 0.9385

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.05

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), PanelApp Australia, 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_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.3683C>G	p.Pro1228Arg	missense_variant, splice_region_variant	Exon 31 of 56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.3719C>G	p.Pro1240Arg	missense_variant, splice_region_variant	Exon 30 of 55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOG	ENST00000399397.6 link	c.3683C>G	p.Pro1228Arg	missense_variant, splice_region_variant	Exon 31 of 56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 link	c.3719C>G	p.Pro1240Arg	missense_variant, splice_region_variant	Exon 30 of 55	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000342528.2 link	n.1048-2539C>G		intron_variant	Intron 7 of 21	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1398358

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

689700

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31596

American (AMR)

AF:

0.00

AC:

AN:

35706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25180

East Asian (EAS)

AF:

0.00

AC:

AN:

35736

South Asian (SAS)

AF:

0.00

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48226

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1078964

Other (OTH)

AF:

0.00

AC:

AN:

58018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.71

T;T

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.43

MutationAssessor

Pathogenic

3.1

M;.

PhyloP100

7.0

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-5.0

D;.

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.0030

D;D

Vest4

0.90

MutPred

0.85

Gain of relative solvent accessibility (P = 0.1259);.;

MVP

0.64

ClinPred

0.99

GERP RS

5.3

Varity_R

0.45

gMVP

0.85

Mutation Taster

=42/58

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.94

dbscSNV1_RF

Benign

0.65

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over