rs1396310498

Positions:

• chr11-17553473-C-A
• chr11-17553473-C-G
• chr11-17553473-C-T

Variant summary

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

The NM_001292063.2(OTOG):​c.494C>A​(p.Thr165Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000764 in 1,308,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.02

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=0.31009907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.494C>A	p.Thr165Asn	missense_variant	6/56	ENST00000399397.6
OTOG	NM_001277269.2	c.530C>A	p.Thr177Asn	missense_variant	5/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.494C>A	p.Thr165Asn	missense_variant	6/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.530C>A	p.Thr177Asn	missense_variant	5/55	5		A2
OTOG	ENST00000498332.5	n.400C>A		non_coding_transcript_exon_variant	5/16	5
OTOG	ENST00000428619.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000125 AC: 1 AN: 80046 Hom.: 0 AF XY: 0.0000248 AC XY: 1 AN XY: 40370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000863

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.64e-7 AC: 1 AN: 1308186 Hom.: 0 Cov.: 32 AF XY: 0.00000157 AC XY: 1 AN XY: 635292

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.65e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Jul 25, 2017

The p.Thr177Asn variant in OTOG has not been previously reported in individuals with hearing loss, but has been identified in 1/11462 of Latino chromosomes by t he Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). Alth ough this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and co nservation analyses do not provide strong support for or against an impact to th e protein. In summary, the clinical significance of the p.Thr177Asn variant is u ncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 28, 2023

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Benign	0.23
Sift	Uncertain	0.019	D;.
Sift4G	Uncertain	0.015	D;D
Vest4		0.59
MutPred		0.63		Loss of ubiquitination at K173 (P = 0.1191);.;
MVP		0.20
ClinPred		0.34	T
GERP RS		2.5
Varity_R		0.15
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs1396310498; hg19: chr11-17575020;