rs876657940

chr11-17608296-ATGCCAAGCCCTCGGGGGC-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_001292063.2(OTOG):c.4162_4179del(p.Lys1388_Ala1393del) variant causes a inframe deletion, splice region change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: OTOG NM_001292063.2 inframe_deletion, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.17

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001292063.2.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.4162_4179del	p.Lys1388_Ala1393del	inframe_deletion, splice_region_variant	34/56	ENST00000399397.6
OTOG	NM_001277269.2	c.4198_4215del	p.Lys1400_Ala1405del	inframe_deletion, splice_region_variant	33/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.4162_4179del	p.Lys1388_Ala1393del	inframe_deletion, splice_region_variant	34/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.4198_4215del	p.Lys1400_Ala1405del	inframe_deletion, splice_region_variant	33/55	5		A2
OTOG	ENST00000342528.2	n.1500_1517del		splice_region_variant, non_coding_transcript_exon_variant	10/22	2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

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

Jan 03, 2016

The p.Lys1400_Ala1405del in OTOG has not been previously reported in individuals with hearing loss and is absent from large population studies, though the abili ty of these studies to accurately detect indels may be limited. This variant is a deletion of 6 amino acids at position 1400 and is not predicted to alter the p rotein reading-frame. It is unclear if this in-frame deletion will impact the no rmal function of the OTOG protein. In summary, the clinical significance of the p.Lys1400_Ala1405del variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657940; hg19: chr11-17629843;