rs369768224

Variant names:

• chr11-17610121-G-A
• rs369768224
• NM_001292063.2:c.4821G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-17610121-G-A
• chr11-17610121-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Very_Strong BP7 BS2_Supporting

The NM_001292063.2(OTOG):​c.4821G>A​(p.Ser1607Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000942 in 1,550,498 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (2 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.80

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 11-17610121-G-A is Benign according to our data. Variant chr11-17610121-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 517546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.8 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.4821G>A	p.Ser1607Ser	synonymous_variant	Exon 36 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.4857G>A	p.Ser1619Ser	synonymous_variant	Exon 35 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.4821G>A	p.Ser1607Ser	synonymous_variant	Exon 36 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.4857G>A	p.Ser1619Ser	synonymous_variant	Exon 35 of 55	5		ENSP00000382323.2
OTOG	ENST00000342528.2	n.2159G>A		non_coding_transcript_exon_variant	Exon 12 of 22	2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152026 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000355 AC: 53 AN: 149242 AF XY: 0.000324

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00126

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000185

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000109

Gnomad OTH exome AF: 0.00323

GnomAD4 exome AF: 0.000101 AC: 141 AN: 1398352 Hom.: 2 Cov.: 32 AF XY: 0.000101 AC XY: 70 AN XY: 689716

African (AFR) AF: 0.0000316 AC: 1 AN: 31598

American (AMR) AF: 0.00143 AC: 51 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48224

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5698

European-Non Finnish (NFE) AF: 0.0000732 AC: 79 AN: 1078964

Other (OTH) AF: 0.000121 AC: 7 AN: 58014

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

African (AFR) AF: 0.0000241 AC: 1 AN: 41500

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000494 Hom.: 0

Bravo AF: 0.0000680

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 05, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Aug 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ser1619Ser in exon 35 of OTOG: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 1/5318 European c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs369768224). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.052
DANN	Benign	0.55
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism

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: rs369768224; hg19: chr11-17631668; COSMIC: COSV61129249;