rs553479177

chr11-17610351-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001292063.2(OTOG):c.5051C>T(p.Pro1684Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000206 in 1,550,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P1684P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0890

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010405958).
• BP6: Variant 11-17610351-C-T is Benign according to our data. Variant chr11-17610351-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 227783.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.5051C>T	p.Pro1684Leu	missense_variant	36/56	ENST00000399397.6
OTOG	NM_001277269.2	c.5087C>T	p.Pro1696Leu	missense_variant	35/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.5051C>T	p.Pro1684Leu	missense_variant	36/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.5087C>T	p.Pro1696Leu	missense_variant	35/55	5		A2
OTOG	ENST00000342528.2	n.2389C>T		non_coding_transcript_exon_variant	12/22	2

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000334 AC: 5 AN: 149496 Hom.: 0 AF XY: 0.0000373 AC XY: 3 AN XY: 80440

Gnomad AFR exome AF: 0.000146

Gnomad AMR exome AF: 0.0000407

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: 0.00

Gnomad OTH exome AF: 0.000693

GnomAD4 exome AF: 0.00000858 AC: 12 AN: 1398374 Hom.: 0 Cov.: 65 AF XY: 0.00000435 AC XY: 3 AN XY: 689712

Gnomad4 AFR exome AF: 0.0000316

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000517

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74498

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Bravo AF: 0.000272

ExAC AF: 0.0000291 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2015

p.Pro1696Leu in exon 35 of OTOG: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, rabbit, pika, and elephant shrew have a leucine (Leu) at this position. In addition, computational prediction tools do not suggest a high likelihood of im pact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	7.5
Dann	Benign	0.72
DEOGEN2	Benign	0.038	T;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.41	N;.
REVEL	Benign	0.062
Sift	Benign	0.16	T;.
Sift4G	Benign	0.19	T;T
Vest4		0.070
MutPred		0.37		Loss of glycosylation at T1697 (P = 0.0408);.;
MVP		0.37
ClinPred		0.015	T
GERP RS		2.6
Varity_R		0.030
gMVP		0.28

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: rs553479177; hg19: chr11-17631898; COSMIC: COSV61133868;