chr11-17574878-T-TAACTGGACACCC

Variant names:

• chr11-17574878-T-TAACTGGACACCC
• rs876657656
• NM_001292063.2:c.2453_2454insACTGGACACCCA

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_001292063.2(OTOG):​c.2453_2454insACTGGACACCCA​(p.Tyr818delinsTerLeuAspThrHis) variant causes a stop gained, disruptive inframe insertion change. The variant allele was found at a frequency of 0.0000111 in 1,537,294 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000271253: disruption of Otog in mice resulted in deafness supporting of a loss-of-function mechanism for the disease (Simmler 2000).". Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: OTOG NM_001292063.2 stop_gained, disruptive_inframe_insertion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.58
• 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 20 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: SCV000271253: disruption of Otog in mice resulted in deafness supporting of a loss-of-function mechanism for the disease (Simmler 2000).
• PP5: Variant 11-17574878-T-TAACTGGACACCC is Pathogenic according to our data. Variant chr11-17574878-T-TAACTGGACACCC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 228283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.2453_2454insACTGGACACCCA	p.Tyr818delinsTerLeuAspThrHis	stop_gained disruptive_inframe_insertion	Exon 20 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.2489_2490insACTGGACACCCA	p.Tyr830delinsTerLeuAspThrHis	stop_gained disruptive_inframe_insertion	Exon 19 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.2453_2454insACTGGACACCCA	p.Tyr818delinsTerLeuAspThrHis	stop_gained disruptive_inframe_insertion	Exon 20 of 56	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.2489_2490insACTGGACACCCA	p.Tyr830delinsTerLeuAspThrHis	stop_gained disruptive_inframe_insertion	Exon 19 of 55	ENSP00000382323.2	Q6ZRI0-1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000810 AC: 11 AN: 135794 AF XY: 0.0000552

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000425

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000256

GnomAD4 exome AF: 0.0000108 AC: 15 AN: 1385094 Hom.: 0 Cov.: 32 AF XY: 0.00000733 AC XY: 5 AN XY: 681774

African (AFR) AF: 0.00 AC: 0 AN: 31310

American (AMR) AF: 0.000431 AC: 15 AN: 34818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24250

East Asian (EAS) AF: 0.00 AC: 0 AN: 35326

South Asian (SAS) AF: 0.00 AC: 0 AN: 77060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5648

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071636

Other (OTH) AF: 0.00 AC: 0 AN: 57388

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.000131 AC: 2 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Autosomal recessive nonsyndromic hearing loss 18B (1)
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.6
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs876657656; hg19: chr11-17596425;