rs764931529

Positions:

• chr11-17606108-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3 BS2_Supporting

The NM_001292063.2(OTOG):​c.4129C>T​(p.Arg1377Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000829 in 1,544,008 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic 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. R1377H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000086 (2 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.96

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: MetaRNN computational evidence supports a deleterious effect, 0.825
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.4129C>T	p.Arg1377Cys	missense_variant	33/56	ENST00000399397.6
OTOG	NM_001277269.2	c.4165C>T	p.Arg1389Cys	missense_variant	32/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.4129C>T	p.Arg1377Cys	missense_variant	33/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.4165C>T	p.Arg1389Cys	missense_variant	32/55	5		A2
OTOG	ENST00000342528.2	n.1467C>T		non_coding_transcript_exon_variant	9/22	2

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152236 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000138 AC: 20 AN: 144624 Hom.: 0 AF XY: 0.000193 AC XY: 15 AN XY: 77814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000914

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000855 AC: 119 AN: 1391772 Hom.: 2 Cov.: 35 AF XY: 0.000107 AC XY: 73 AN XY: 685312

Gnomad4 AFR exome AF: 0.0000318

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000400

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000251

Gnomad4 OTH exome AF: 0.000139

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152236 Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.0000189

ExAC AF: 0.000327 AC: 7

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

Jun 29, 2015

The p.Arg1389Cys variant in OTOG has not been previously reported in individuals with hearing loss, but has been identified in 0.1% (7/5540) of South Asian chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs764931529). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summar y, the clinical significance of the p.Arg1389Cys variant is uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 31, 2021

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	0.19
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.0	D;.
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Vest4		0.60
MutPred		0.80		Loss of methylation at R1389 (P = 0.0342);.;
MVP		0.54
ClinPred		0.83	D
GERP RS		4.0
Varity_R		0.70
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs764931529; hg19: chr11-17627655;