11-17606135-G-T

Variant names:

• chr11-17606135-G-T
• rs876657939
• NM_001292063.2:c.4156G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001292063.2(OTOG):​c.4156G>T​(p.Asp1386Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000218 in 1,374,806 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1386N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.76
• 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	NM_001292063.2	MANE Select	c.4156G>T	p.Asp1386Tyr	missense splice_region	Exon 33 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.4192G>T	p.Asp1398Tyr	missense splice_region	Exon 32 of 55	NP_001264198.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.4156G>T	p.Asp1386Tyr	missense splice_region	Exon 33 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.4192G>T	p.Asp1398Tyr	missense splice_region	Exon 32 of 55	ENSP00000382323.2
	OTOG	ENST00000342528.2	TSL:2	n.1494G>T		splice_region non_coding_transcript_exon	Exon 9 of 22

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000218 AC: 3 AN: 1374806 Hom.: 0 Cov.: 35 AF XY: 0.00000148 AC XY: 1 AN XY: 674144

African (AFR) AF: 0.00 AC: 0 AN: 31196

American (AMR) AF: 0.00 AC: 0 AN: 34932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24076

East Asian (EAS) AF: 0.00 AC: 0 AN: 35314

South Asian (SAS) AF: 0.00 AC: 0 AN: 76018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4248

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1065058

Other (OTH) AF: 0.0000176 AC: 1 AN: 56872

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	35
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.8
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.29
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.024	D
Vest4		0.54
MutPred		0.51		Loss of ubiquitination at K1400 (P = 0.0363)
MVP		0.54
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.33
gMVP		0.80
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.40		Position offset: -34

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

Other links and lift over

dbSNP: rs876657939; hg19: chr11-17627682;