rs115772736

chr11-17559660-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001292063.2(OTOG):c.1340A>G(p.Asn447Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000444 in 1,550,190 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense, splice_region
• Scores: Splicing: ADA: 0.1068
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.85

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010245383).
• BP6: Variant 11-17559660-A-G is Benign according to our data. Variant chr11-17559660-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 504781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.1340A>G	p.Asn447Ser	missense_variant, splice_region_variant	12/56	ENST00000399397.6
OTOG	NM_001277269.2	c.1376A>G	p.Asn459Ser	missense_variant, splice_region_variant	11/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.1340A>G	p.Asn447Ser	missense_variant, splice_region_variant	12/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.1376A>G	p.Asn459Ser	missense_variant, splice_region_variant	11/55	5		A2
OTOG	ENST00000498332.5	n.1246A>G		splice_region_variant, non_coding_transcript_exon_variant	11/16	5

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 330 AN: 152036 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00758

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000474 AC: 71 AN: 149798 Hom.: 0 AF XY: 0.000348 AC XY: 28 AN XY: 80468

Gnomad AFR exome AF: 0.00800

Gnomad AMR exome AF: 0.000488

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: 0.0000180

Gnomad OTH exome AF: 0.000461

GnomAD4 exome AF: 0.000252 AC: 353 AN: 1398038 Hom.: 0 Cov.: 32 AF XY: 0.000203 AC XY: 140 AN XY: 689526

Gnomad4 AFR exome AF: 0.00807

Gnomad4 AMR exome AF: 0.000476

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.0000505

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000130

Gnomad4 OTH exome AF: 0.00100

GnomAD4 genome AF: 0.00221 AC: 336 AN: 152152 Hom.: 2 Cov.: 32 AF XY: 0.00211 AC XY: 157 AN XY: 74388

Gnomad4 AFR AF: 0.00770

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00121 Hom.: 0

Bravo AF: 0.00241

ExAC AF: 0.000494 AC: 13

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 20, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Asn459Ser in exon 11 of OTOG: This variant is not expected to have clinical sign ificance because it has been identified in 3.1% (6/194) of Luhya (Kenyan) chromo somes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.n ih.gov/projects/SNP; dbSNP rs115772736). -

OTOG-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 20, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.040	T;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.38	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.95	N;.
REVEL	Benign	0.096
Sift	Uncertain	0.0090	D;.
Sift4G	Uncertain	0.015	D;D
Vest4		0.11
MVP		0.19
ClinPred		0.022	T
GERP RS		4.4
Varity_R		0.053
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.11
dbscSNV1_RF	Benign	0.22
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.23		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs115772736; hg19: chr11-17581207;