rs1032491736

chr11-17570228-G-A

Variant summary

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

The NM_001292063.2(OTOG):c.1793G>A(p.Arg598His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000361 in 1,550,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.56

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=0.3957141).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.1793G>A	p.Arg598His	missense_variant	17/56	ENST00000399397.6
OTOG	NM_001277269.2	c.1829G>A	p.Arg610His	missense_variant	16/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.1793G>A	p.Arg598His	missense_variant	17/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.1829G>A	p.Arg610His	missense_variant	16/55	5		A2
OTOG	ENST00000498332.5	n.1699G>A		non_coding_transcript_exon_variant	16/16	5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152208 Hom.: 0 Cov.: 33

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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000666 AC: 1 AN: 150076 Hom.: 0 AF XY: 0.0000124 AC XY: 1 AN XY: 80566

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000379 AC: 53 AN: 1398396 Hom.: 0 Cov.: 30 AF XY: 0.0000420 AC XY: 29 AN XY: 689728

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000463

Gnomad4 OTH exome AF: 0.0000345

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74360

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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 16, 2017

The p.Arg610His variant in OTOG has not been previously reported in individuals with hearing loss. This variant has been identified in 3/67514 European chromos omes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.or g). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tool s and conservation analysis do not provide strong support for or against an impa ct to the protein. In summary, the clinical significance of the p.Arg610His vari ant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	23
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.069
Eigen_PC	Benign	-0.025
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.40	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	0.74	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.9	D;.
REVEL	Uncertain	0.32
Sift	Benign	0.046	D;.
Sift4G	Uncertain	0.0040	D;D
Vest4		0.36
MutPred		0.74		Loss of MoRF binding (P = 0.0444);.;
MVP		0.37
ClinPred		0.94	D
GERP RS		2.8
Varity_R		0.13
gMVP		0.42

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: rs1032491736; hg19: chr11-17591775; COSMIC: COSV105335543;