rs1193023501

Variant names:

• chr11-17629159-G-A
• rs1193023501
• NM_001292063.2:c.6555G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PS3 PM2 PP5_Moderate

The NM_001292063.2(OTOG):​c.6555G>A​(p.Trp2185*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,398,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000731645: disruption of OTOG in mice resulted in deafness supporting a loss-of-function mechanism for the disease (Simmler 2000).". Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: OTOG NM_001292063.2 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.02
• 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), 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000731645: disruption of OTOG in mice resulted in deafness supporting a loss-of-function mechanism for the disease (Simmler 2000).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-17629159-G-A is Pathogenic according to our data. Variant chr11-17629159-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 517387.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001292063.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	NM_001292063.2	MANE Select	c.6555G>A	p.Trp2185*	stop_gained	Exon 40 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.6591G>A	p.Trp2197*	stop_gained	Exon 39 of 55	NP_001264198.1	Q6ZRI0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.6555G>A	p.Trp2185*	stop_gained	Exon 40 of 56	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.6591G>A	p.Trp2197*	stop_gained	Exon 39 of 55	ENSP00000382323.2	Q6ZRI0-1
	OTOG	ENST00000342528.2	TSL:2	n.3893G>A		non_coding_transcript_exon	Exon 16 of 22

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000672 AC: 1 AN: 148878 AF XY: 0.0000125

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1398064 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 2 AN XY: 689556

African (AFR) AF: 0.00 AC: 0 AN: 31594

American (AMR) AF: 0.00 AC: 0 AN: 35676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.00 AC: 0 AN: 79206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078842

Other (OTH) AF: 0.00 AC: 0 AN: 57980

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	39
DANN	Uncertain	0.99
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Benign	0.69	D
PhyloP100		3.0
Vest4		0.35
GERP RS		3.2
Mutation Taster		=8/192	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1193023501; hg19: chr11-17650706;