11-17547476-T-C

Variant names:

• chr11-17547476-T-C
• rs368841888
• NM_001292063.2:c.94+10T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001292063.2(OTOG):​c.94+10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,350,060 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: OTOG NM_001292063.2 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.906
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019074738).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.94+10T>C		intron_variant	Intron 1 of 55	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.104T>C	p.Val35Ala	missense_variant	Exon 1 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.94+10T>C		intron_variant	Intron 1 of 55	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.104T>C	p.Val35Ala	missense_variant	Exon 1 of 55	5		ENSP00000382323.2

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151536 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000631

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.000335 AC: 5 AN: 14908 AF XY: 0.000243

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: 0.00

Gnomad OTH exome AF: 0.00186

GnomAD4 exome AF: 0.0000684 AC: 82 AN: 1198524 Hom.: 0 Cov.: 31 AF XY: 0.000107 AC XY: 62 AN XY: 579404

African (AFR) AF: 0.00 AC: 0 AN: 24324

American (AMR) AF: 0.00 AC: 0 AN: 13878

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16798

East Asian (EAS) AF: 0.00 AC: 0 AN: 28200

South Asian (SAS) AF: 0.00121 AC: 59 AN: 48940

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26594

Middle Eastern (MID) AF: 0.000823 AC: 4 AN: 4860

European-Non Finnish (NFE) AF: 0.0000152 AC: 15 AN: 985784

Other (OTH) AF: 0.0000814 AC: 4 AN: 49146

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151536 Hom.: 0 Cov.: 32 AF XY: 0.0000541 AC XY: 4 AN XY: 73932

African (AFR) AF: 0.00 AC: 0 AN: 41198

American (AMR) AF: 0.00 AC: 0 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.000631 AC: 3 AN: 4758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67870

Other (OTH) AF: 0.000481 AC: 1 AN: 2078

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.000226 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 09, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.8
DANN	Benign	0.77
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.91
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.013
Sift	Benign	0.39	T
Sift4G	Benign	1.0	T
Vest4		0.024
MutPred		0.24		Loss of stability (P = 0.0399);
MVP		0.030
ClinPred		0.0091	T
GERP RS		2.2
PromoterAI		0.0056	Neutral
Varity_R		0.030
gMVP		0.086
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs368841888; hg19: chr11-17569023;