rs7936354

chr11-17594108-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001292063.2(OTOG):c.3350C>T(p.Pro1117Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00757 in 1,550,440 control chromosomes in the GnomAD database, including 736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1117P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.039 (418 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (318 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.63

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002730459).
• BP6: Variant 11-17594108-C-T is Benign according to our data. Variant chr11-17594108-C-T is described in ClinVar as [Benign]. Clinvar id is 226884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.3350C>T	p.Pro1117Leu	missense_variant	28/56	ENST00000399397.6
OTOG	NM_001277269.2	c.3386C>T	p.Pro1129Leu	missense_variant	27/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.3350C>T	p.Pro1117Leu	missense_variant	28/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.3386C>T	p.Pro1129Leu	missense_variant	27/55	5		A2
OTOG	ENST00000342528.2	n.715C>T		non_coding_transcript_exon_variant	5/22	2

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5921 AN: 152080 Hom.: 418 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.0335

GnomAD3 exomes AF: 0.00824 AC: 1230 AN: 149206 Hom.: 74 AF XY: 0.00658 AC XY: 529 AN XY: 80368

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.00745

Gnomad ASJ exome AF: 0.00131

Gnomad EAS exome AF: 0.0000927

Gnomad SAS exome AF: 0.000355

Gnomad FIN exome AF: 0.0000595

Gnomad NFE exome AF: 0.000654

Gnomad OTH exome AF: 0.00765

GnomAD4 exome AF: 0.00416 AC: 5816 AN: 1398242 Hom.: 318 Cov.: 32 AF XY: 0.00368 AC XY: 2539 AN XY: 689648

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.00815

Gnomad4 ASJ exome AF: 0.000755

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000517

Gnomad4 FIN exome AF: 0.0000208

Gnomad4 NFE exome AF: 0.000468

Gnomad4 OTH exome AF: 0.00940

GnomAD4 genome AF: 0.0389 AC: 5927 AN: 152198 Hom.: 418 Cov.: 32 AF XY: 0.0375 AC XY: 2788 AN XY: 74440

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0145

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.0331

Alfa AF: 0.0108 Hom.: 154

Bravo AF: 0.0450

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.00710 AC: 144

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Pro1129Leu in exon 27 of OTOG: This variant is not expected to have clinical sig nificance because it has been identified in 15.5% (30/194) of Luhya (Kenyan) chr omosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nl m.nih.gov/projects/SNP; dbSNP rs7936354). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.3	D;.
REVEL	Uncertain	0.48
Sift	Uncertain	0.0050	D;.
Sift4G	Uncertain	0.0060	D;D
Vest4		0.56
MVP		0.74
ClinPred		0.019	T
GERP RS		4.6
Varity_R		0.32
gMVP		0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs7936354; hg19: chr11-17615655;