rs876657553

Variant names:

• chr11-17586546-C-T
• rs876657553
• NM_001292063.2:c.2832C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_001292063.2(OTOG):​c.2832C>T​(p.Phe944Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,285,268 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.497
• Publications: 0 publications found

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]

OTOG Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 18B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.1).
• BP6: Variant 11-17586546-C-T is Benign according to our data. Variant chr11-17586546-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 227773.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.497 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.2832C>T	p.Phe944Phe	synonymous_variant	Exon 24 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.2868C>T	p.Phe956Phe	synonymous_variant	Exon 23 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.2832C>T	p.Phe944Phe	synonymous_variant	Exon 24 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.2868C>T	p.Phe956Phe	synonymous_variant	Exon 23 of 55	5		ENSP00000382323.2
OTOG	ENST00000342528.2	n.336C>T		non_coding_transcript_exon_variant	Exon 2 of 22	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000171 AC: 22 AN: 1285268 Hom.: 0 Cov.: 29 AF XY: 0.0000175 AC XY: 11 AN XY: 629838

African (AFR) AF: 0.00 AC: 0 AN: 26740

American (AMR) AF: 0.00 AC: 0 AN: 21424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21050

East Asian (EAS) AF: 0.00 AC: 0 AN: 29262

South Asian (SAS) AF: 0.00 AC: 0 AN: 59908

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5330

European-Non Finnish (NFE) AF: 0.0000215 AC: 22 AN: 1022916

Other (OTH) AF: 0.00 AC: 0 AN: 52886

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 17, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Phe956Phe in exon 23 of OTOG: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	9.2
DANN	Uncertain	1.0
PhyloP100		0.50

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

Other links and lift over

dbSNP: rs876657553; hg19: chr11-17608093; COSMIC: COSV61128367;