rs552304627

Variant names:

• chr11-17553211-G-A
• rs552304627
• NM_001292063.2:c.385G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_001292063.2(OTOG):​c.385G>A​(p.Val129Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000906 in 1,550,382 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00083 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00091 (3 hom.)
• Consequence: OTOG NM_001292063.2 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:1
• Conservation: PhyloP100: 9.60

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.385G>A	p.Val129Met	missense_variant, splice_region_variant	Exon 5 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.421G>A	p.Val141Met	missense_variant, splice_region_variant	Exon 4 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.385G>A	p.Val129Met	missense_variant, splice_region_variant	Exon 5 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.421G>A	p.Val141Met	missense_variant, splice_region_variant	Exon 4 of 55	5		ENSP00000382323.2
OTOG	ENST00000428619.1	c.202G>A	p.Val68Met	missense_variant, splice_region_variant	Exon 3 of 4	3		ENSP00000399057.2
OTOG	ENST00000498332.5	n.291G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 16	5

Frequencies

GnomAD3 genomes AF: 0.000835 AC: 127 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000880 AC: 130 AN: 147698 Hom.: 1 AF XY: 0.000892 AC XY: 71 AN XY: 79616

Gnomad AFR exome AF: 0.000148

Gnomad AMR exome AF: 0.00187

Gnomad ASJ exome AF: 0.000120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000888

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000914 AC: 1278 AN: 1398080 Hom.: 3 Cov.: 32 AF XY: 0.000899 AC XY: 620 AN XY: 689586

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.0000795

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000126

Gnomad4 FIN exome AF: 0.0000416

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.000931

GnomAD4 genome AF: 0.000834 AC: 127 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.000859 AC XY: 64 AN XY: 74474

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00118

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000824 Hom.: 0

Bravo AF: 0.00110

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000282 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

OTOG: PP3, BS1:Supporting -

Dec 08, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 21, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val141Met variant in OTOG has been previously reported in 1 individual with hearing loss, but a variant affecting the remaining copy of OTOG was not identified (LMM data). This variant has been reported by other clinical laboratories in ClinVar (Variation ID 229094) and has been identified in 1.3% (4/316) of Middle Eastern and 0.17% (27/15286) of Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant is located in the last base of the exon, which is part of the 5’ splice region. Splice site computational tools suggest a possible impact to splicing, however, this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Val141Met variant is uncertain. ACMG/AMP Criteria applied: BS1_Supporting. -

Jan 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 141 of the OTOG protein (p.Val141Met). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is present in population databases (rs552304627, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with OTOG-related conditions. ClinVar contains an entry for this variant (Variation ID: 229094). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Meniere disease Pathogenic:1

Jan 01, 2020

Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: case-control

- -

not specified Uncertain:1

May 04, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

OTOG-related disorder Uncertain:1

Apr 24, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The OTOG c.421G>A variant is predicted to result in the amino acid substitution p.Val141Met. This variant was reported in an individual with non-syndromic hearing loss (Table S6, Quaio et al. 2022. PubMed ID: 36147510). This variant is reported in 0.19% of alleles in individuals of Latino descent in gnomAD, including one homozygous individual. While we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Autosomal recessive nonsyndromic hearing loss 18B Uncertain:1

Jan 16, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.030	T;T;T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.3	M;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.3	N;.;.
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D;.;.
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.50
MVP		0.29
ClinPred		0.084	T
GERP RS		5.4
Varity_R		0.31
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.15		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

Other links and lift over

dbSNP: rs552304627; hg19: chr11-17574758; COSMIC: COSV68037922; COSMIC: COSV68037922;