chr11-17547410-G-A

Variant names:

• chr11-17547410-G-A
• rs1851830866
• NM_001292063.2:c.38G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001292063.2(OTOG):​c.38G>A​(p.Cys13Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000787 in 1,269,880 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: not found (cov: 32)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.69
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22805065).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.38G>A	p.Cys13Tyr	missense_variant	Exon 1 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.38G>A	p.Cys13Tyr	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.38G>A	p.Cys13Tyr	missense_variant	Exon 1 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.38G>A	p.Cys13Tyr	missense_variant	Exon 1 of 55	5		ENSP00000382323.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.87e-7 AC: 1 AN: 1269880 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 622308

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25936

American (AMR) AF: 0.00 AC: 0 AN: 21210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19996

East Asian (EAS) AF: 0.00 AC: 0 AN: 29448

South Asian (SAS) AF: 0.00 AC: 0 AN: 61452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4794

European-Non Finnish (NFE) AF: 9.76e-7 AC: 1 AN: 1025110

Other (OTH) AF: 0.00 AC: 0 AN: 52332

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 13 of the OTOG protein (p.Cys13Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with OTOG-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	23
DANN	Benign	0.84
DEOGEN2	Benign	0.056	T;.
Eigen	Benign	-0.048
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.52	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;.
PhyloP100		4.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.11
Sift	Uncertain	0.0040	D;.
Sift4G	Pathogenic	0.0	D;D
Vest4		0.26
MutPred		0.31		Gain of catalytic residue at P17 (P = 0.1082);Gain of catalytic residue at P17 (P = 0.1082);
MVP		0.19
ClinPred		0.45	T
GERP RS		4.2
PromoterAI		-0.021	Neutral
Varity_R		0.52
gMVP		0.17
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1851830866; hg19: chr11-17568957;