rs876657945

chr11-17640919-CC-AT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001292063.2(OTOG):c.8018_8019delinsAT(p.Ala2673Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. A2673A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.07

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.8018_8019delinsAT	p.Ala2673Asp	missense_variant	51/56	ENST00000399397.6
OTOG	NM_001277269.2	c.8054_8055delinsAT	p.Ala2685Asp	missense_variant	50/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.8018_8019delinsAT	p.Ala2673Asp	missense_variant	51/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.8054_8055delinsAT	p.Ala2685Asp	missense_variant	50/55	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 01, 2022	BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2023	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2685 of the OTOG protein (p.Ala2685Asp). This variant is present in population databases (no rsID available, gnomAD 0.03%). 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: 229106). 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2023	In silico analysis supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 22, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.Ala2685Asp va riant in OTOG has been previously reported by our laboratory in one individual w ith hearing loss, in whom a variant affecting the remaining copy of the gene was not identified. Although the coding change identified in this individual (c.805 4_8055delinsAT) was not reported in large population databases, the two componen t variants, c.8054C>A and c.8055C>T were reported in 1/4874 and 1/4880 European chromosomes, respectively, by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs563948391 and rs531303093). While these variants a re likely to represent the c.8054_8055delinsAT variant, at this time we cannot c onfirm that the two variants were identified on the same chromosome in the ExAC cohort. Furthermore, alanine (Ala) at position 2685 is conserved in mammals but not in evolutionarily distant species, with >15 species of birds carry an aspart ic acid (Asp) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools do not provide strong evide nce for or against an impact to the protein. In summary, while the clinical sign ificance of the p.Ala2685Asp variant is uncertain, the conservation data suggest s that it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs876657945; hg19: chr11-17662466;