rs61730948

Positions:

• chr11-17641918-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001292063.2(OTOG):​c.8262C>T​(p.Phe2754=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00405 in 1,550,294 control chromosomes in the GnomAD database, including 223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (125 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (98 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.15

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 11-17641918-C-T is Benign according to our data. Variant chr11-17641918-C-T is described in ClinVar as [Benign]. Clinvar id is 226918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0687 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.8262C>T	p.Phe2754=	synonymous_variant	52/56	ENST00000399397.6
OTOG	NM_001277269.2	c.8298C>T	p.Phe2766=	synonymous_variant	51/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.8262C>T	p.Phe2754=	synonymous_variant	52/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.8298C>T	p.Phe2766=	synonymous_variant	51/55	5		A2

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3114 AN: 152098 Hom.: 125 Cov.: 32

Gnomad AFR AF: 0.0708

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00687

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.00434 AC: 646 AN: 148748 Hom.: 21 AF XY: 0.00361 AC XY: 289 AN XY: 80152

Gnomad AFR exome AF: 0.0743

Gnomad AMR exome AF: 0.00395

Gnomad ASJ exome AF: 0.00108

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000266

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000383

Gnomad OTH exome AF: 0.00256

GnomAD4 exome AF: 0.00226 AC: 3153 AN: 1398078 Hom.: 98 Cov.: 33 AF XY: 0.00203 AC XY: 1401 AN XY: 689576

Gnomad4 AFR exome AF: 0.0753

Gnomad4 AMR exome AF: 0.00423

Gnomad4 ASJ exome AF: 0.000676

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000235

Gnomad4 OTH exome AF: 0.00531

GnomAD4 genome AF: 0.0205 AC: 3119 AN: 152216 Hom.: 125 Cov.: 32 AF XY: 0.0193 AC XY: 1439 AN XY: 74434

Gnomad4 AFR AF: 0.0708

Gnomad4 AMR AF: 0.00686

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.00918 Hom.: 21

Bravo AF: 0.0233

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 10, 2018	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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Phe2766Phe in exon 51 of OTOG: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 11.9% (23/194) of L uhya (Kenyan) chromosomes from a broad population by the 1000 Genomes Project (h ttp://www.ncbi.nlm.nih.gov/projects/SNP; dbSNP rs61730948). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	8.6
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs61730948; hg19: chr11-17663465;