rs73418062

Positions:

• chr11-17559535-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001292063.2(OTOG):​c.1215T>C​(p.Thr405=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,550,654 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (11 hom.)
• Consequence: OTOG NM_001292063.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.001866
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0720

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 11-17559535-T-C is Benign according to our data. Variant chr11-17559535-T-C is described in ClinVar as [Benign]. Clinvar id is 226862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.072 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00557 (848/152302) while in subpopulation AFR AF= 0.0196 (816/41558). AF 95% confidence interval is 0.0185. There are 16 homozygotes in gnomad4. There are 406 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.1215T>C	p.Thr405=	splice_region_variant, synonymous_variant	12/56	ENST00000399397.6
OTOG	NM_001277269.2	c.1251T>C	p.Thr417=	splice_region_variant, synonymous_variant	11/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.1215T>C	p.Thr405=	splice_region_variant, synonymous_variant	12/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.1251T>C	p.Thr417=	splice_region_variant, synonymous_variant	11/55	5		A2
OTOG	ENST00000498332.5	n.1121T>C		splice_region_variant, non_coding_transcript_exon_variant	11/16	5

Frequencies

GnomAD3 genomes AF: 0.00557 AC: 847 AN: 152184 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

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: 0.00334

GnomAD3 exomes AF: 0.00123 AC: 184 AN: 149356 Hom.: 1 AF XY: 0.000995 AC XY: 80 AN XY: 80408

Gnomad AFR exome AF: 0.0234

Gnomad AMR exome AF: 0.000773

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000222

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000589 AC: 823 AN: 1398352 Hom.: 11 Cov.: 33 AF XY: 0.000523 AC XY: 361 AN XY: 689698

Gnomad4 AFR exome AF: 0.0216

Gnomad4 AMR exome AF: 0.00104

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000102

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00557 AC: 848 AN: 152302 Hom.: 16 Cov.: 32 AF XY: 0.00545 AC XY: 406 AN XY: 74482

Gnomad4 AFR AF: 0.0196

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00303 Hom.: 2

Bravo AF: 0.00667

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Thr417Thr in exon 11 of OTOG: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 1.2% (6/492) of Afri can chromosomes from a broad population by the 1000 Genomes Project (http://www. ncbi.nlm.nih.gov/projects/SNP; dbSNP rs73418062). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.6
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0019
dbscSNV1_RF	Benign	0.16
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: rs73418062; hg19: chr11-17581082;