11-17547541-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001292063.2(OTOG):c.94+75G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000176 in 1,277,382 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (2 hom.)
• Consequence: OTOG NM_001292063.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.0950

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052696764).
• BP6: Variant 11-17547541-G-T is Benign according to our data. Variant chr11-17547541-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 506139.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.94+75G>T		intron_variant		ENST00000399397.6
OTOG	NM_001277269.2	c.169G>T	p.Ala57Ser	missense_variant	1/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.94+75G>T		intron_variant		5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.169G>T	p.Ala57Ser	missense_variant	1/55	5		A2

Frequencies

GnomAD3 genomes AF: 0.000316 AC: 48 AN: 152114 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: 0.00736

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000285 AC: 1 AN: 3514 Hom.: 0 AF XY: 0.000503 AC XY: 1 AN XY: 1988

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000990

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000157 AC: 177 AN: 1125150 Hom.: 2 Cov.: 31 AF XY: 0.000160 AC XY: 86 AN XY: 536268

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000949

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00472

Gnomad4 SAS exome AF: 0.000711

Gnomad4 FIN exome AF: 0.000130

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000502

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74420

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00738

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000480

ExAC AF: 0.000117 AC: 2

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 14, 2017

p.Ala57Ser in exon 1 of OTOG: This variant is not expected to have clinical sign ificance because it has been identified in 0.8% (14/1838) of East Asian chromoso mes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org ; dbSNP rs550807341). -

OTOG-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	2.8
Dann	Benign	0.66
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.38	N
REVEL	Benign	0.013
Sift	Benign	0.73	T
Sift4G	Benign	0.39	T
Vest4		0.034
MutPred		0.17		Gain of phosphorylation at A57 (P = 0.0183);
MVP		0.040
ClinPred		0.0084	T
GERP RS		-0.76
Varity_R		0.039
gMVP		0.097

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs550807341; hg19: chr11-17569088;