rs757588809

chr11-17594117-T-Cchr11-17594117-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001292063.2(OTOG):c.3359T>C(p.Leu1120Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,550,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1120R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.46

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3378933).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.3359T>C	p.Leu1120Pro	missense_variant	28/56	ENST00000399397.6
OTOG	NM_001277269.2	c.3395T>C	p.Leu1132Pro	missense_variant	27/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.3359T>C	p.Leu1120Pro	missense_variant	28/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.3395T>C	p.Leu1132Pro	missense_variant	27/55	5		A2
OTOG	ENST00000342528.2	n.724T>C		non_coding_transcript_exon_variant	5/22	2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000871 AC: 13 AN: 149212 Hom.: 0 AF XY: 0.0000622 AC XY: 5 AN XY: 80376

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000407

Gnomad ASJ exome AF: 0.000239

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000163

Gnomad OTH exome AF: 0.000232

GnomAD4 exome AF: 0.000157 AC: 219 AN: 1398264 Hom.: 0 Cov.: 32 AF XY: 0.000151 AC XY: 104 AN XY: 689652

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.0000560

Gnomad4 ASJ exome AF: 0.000119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000623

Gnomad4 NFE exome AF: 0.000191

Gnomad4 OTH exome AF: 0.0000517

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74334

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.000113

ExAC AF: 0.0000492 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 30, 2023	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1132 of the OTOG protein (p.Leu1132Pro). This variant is present in population databases (rs757588809, gnomAD 0.02%). 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: 517377). 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	Dec 10, 2020	In silico analysis supports that this missense variant has a deleterious effect on 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

May 16, 2017

The p.Leu1132Pro variant in OTOG has not been previously reported in individuals with hearing loss, but has been identified in 12/67064 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs757588809). Although this variant has been seen in the general population, it s frequency is not high enough to rule out a pathogenic role. Computational pred iction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogeni city. In summary, the clinical significance of the p.Leu1132Pro variant is uncer tain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.18
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.1	D;.
REVEL	Uncertain	0.29
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0030	D;D
Vest4		0.57
MVP		0.53
ClinPred		0.61	D
GERP RS		5.5
Varity_R		0.83
gMVP		0.80

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: rs757588809; hg19: chr11-17615664;