11-17599671-C-T

Position:

• chr11-17599671-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3 BP6 BS2

The NM_001292063.2(OTOG):​c.3683C>T​(p.Pro1228Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00483 in 1,550,638 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (17 hom.)
• Consequence: OTOG NM_001292063.2 missense, splice_region
• Scores: Splicing: ADA: 0.9945
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 7.05

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 10: BayesDel_noAF, Cadd, Dann, dbscSNV1_ADA, dbscSNV1_RF, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP6: Variant 11-17599671-C-T is Benign according to our data. Variant chr11-17599671-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229088.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}.
• BS2: High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.3683C>T	p.Pro1228Leu	missense_variant, splice_region_variant	31/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.3719C>T	p.Pro1240Leu	missense_variant, splice_region_variant	30/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.3683C>T	p.Pro1228Leu	missense_variant, splice_region_variant	31/56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.3719C>T	p.Pro1240Leu	missense_variant, splice_region_variant	30/55	5		ENSP00000382323.2
OTOG	ENST00000342528.2	n.1048-2539C>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 502 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00591

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00273 AC: 409 AN: 149550 Hom.: 0 AF XY: 0.00241 AC XY: 194 AN XY: 80466

Gnomad AFR exome AF: 0.000881

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000710

Gnomad FIN exome AF: 0.00196

Gnomad NFE exome AF: 0.00555

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00500 AC: 6985 AN: 1398314 Hom.: 17 Cov.: 31 AF XY: 0.00487 AC XY: 3361 AN XY: 689684

Gnomad4 AFR exome AF: 0.000633

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.000199

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.000896

Gnomad4 FIN exome AF: 0.00290

Gnomad4 NFE exome AF: 0.00599

Gnomad4 OTH exome AF: 0.00379

GnomAD4 genome AF: 0.00330 AC: 502 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.00305 AC XY: 227 AN XY: 74488

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.00591

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00494 Hom.: 0

Bravo AF: 0.00323

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00727 AC: 28

ExAC AF: 0.00132 AC: 30

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	OTOG: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2019	This variant is associated with the following publications: (PMID: 30097855) -

Meniere disease Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)

Jan 01, 2020

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 13, 2017

p.Pro1240Leu in exon 30 of OTOG: This variant is not expected to have clinical significance because it has been identified in 0.6% (384/67268) of European chro mosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute .org; dbSNP rs117005078). Furthermore, this variant has been reported by our la boratory in 10 individuals with hearing loss, including 4 with an alternate gene tic etiology identified. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	T;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.076	T;T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.8	H;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.8	D;.
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.0020	D;D
Vest4		0.90
MVP		0.80
ClinPred		0.11	T
GERP RS		5.3
Varity_R		0.29
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.93
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

Publications

LitVar

Other links and lift over

dbSNP: rs117005078; hg19: chr11-17621218;