rs867891665

chr11-17610120-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001292063.2(OTOG):c.4820C>T(p.Ser1607Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000271 in 1,550,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S1607S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.912

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13865882).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.4820C>T	p.Ser1607Leu	missense_variant	36/56	ENST00000399397.6
OTOG	NM_001277269.2	c.4856C>T	p.Ser1619Leu	missense_variant	35/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.4820C>T	p.Ser1607Leu	missense_variant	36/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.4856C>T	p.Ser1619Leu	missense_variant	35/55	5		A2
OTOG	ENST00000342528.2	n.2158C>T		non_coding_transcript_exon_variant	12/22	2

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000402 AC: 6 AN: 149314 Hom.: 0 AF XY: 0.0000498 AC XY: 4 AN XY: 80380

Gnomad AFR exome AF: 0.000293

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000444

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000545

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000236 AC: 33 AN: 1398348 Hom.: 0 Cov.: 32 AF XY: 0.0000246 AC XY: 17 AN XY: 689708

Gnomad4 AFR exome AF: 0.000253

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.0000207

Gnomad4 NFE exome AF: 0.0000158

Gnomad4 OTH exome AF: 0.0000517

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74300

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000749 Hom.: 0

Bravo AF: 0.000132

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 09, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.Ser1619Leu va riant in OTOG has not been previously reported in individuals with hearing loss. Data from large population studies are insufficient to assess the frequency of this variant. The serine (Ser) at position 1619 is not highly conserved in mamm als and evolutionary distant species. Of note, two mammals (shrew and wallaby) h ave a leucine (Leu) at this position despite high nearby amino acid conservation . Additional computational prediction tools do not provide strong support for o r against an impact to the protein. In summary, while the clinical significance of the p.Ser1619Leu variant is uncertain, the conservation data suggest it is mo re likely to be benign. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 27, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with OTOG-related conditions. ClinVar contains an entry for this variant (Variation ID: 229096). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces serine with leucine at codon 1619 of the OTOG protein (p.Ser1619Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.058	T;.
Eigen	Benign	-0.051
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.8	N;.
REVEL	Benign	0.093
Sift	Uncertain	0.0070	D;.
Sift4G	Benign	0.11	T;T
Vest4		0.20
MVP		0.40
ClinPred		0.12	T
GERP RS		4.4
Varity_R		0.10
gMVP		0.37

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

Other links and lift over

dbSNP: rs867891665; hg19: chr11-17631667; COSMIC: COSV104650808;