rs535970426

chr11-17552079-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001292063.2(OTOG):c.292+4A>C variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.00041 in 1,550,306 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00043 (1 hom.)
• Consequence: OTOG NM_001292063.2 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9929
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.83

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.292+4A>C		splice_donor_region_variant, intron_variant		ENST00000399397.6
OTOG	NM_001277269.2	c.328+4A>C		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.292+4A>C		splice_donor_region_variant, intron_variant		5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.328+4A>C		splice_donor_region_variant, intron_variant		5		A2
OTOG	ENST00000428619.1	c.109+4A>C		splice_donor_region_variant, intron_variant		3
OTOG	ENST00000498332.5	n.198+4A>C		splice_donor_region_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000382

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000188 AC: 28 AN: 149184 Hom.: 0 AF XY: 0.000187 AC XY: 15 AN XY: 80346

Gnomad AFR exome AF: 0.000147

Gnomad AMR exome AF: 0.000448

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: 0.000291

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000431 AC: 603 AN: 1398012 Hom.: 1 Cov.: 30 AF XY: 0.000439 AC XY: 303 AN XY: 689574

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000420

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000207

Gnomad4 NFE exome AF: 0.000533

Gnomad4 OTH exome AF: 0.000207

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74460

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000229 Hom.: 0

Bravo AF: 0.000276

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 10, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 432317). This variant has not been reported in the literature in individuals affected with OTOG-related conditions. This variant is present in population databases (rs535970426, gnomAD 0.04%). This sequence change falls in intron 3 of the OTOG gene. It does not directly change the encoded amino acid sequence of the OTOG protein. It affects a nucleotide within the consensus splice site. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2023	In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 25, 2017

The c.328+4A>C variant in OTOG has not been previously reported in individuals w ith hearing loss, but has been identified in 10/24674 of Latino chromosomes and 17/66944 of European chromosomes by the Genome Aggregation Database (gnomAD, htt p://gnomad.broadinstitute.org/; dbSNP rs535970426). Although this variant has be en seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is located in the 5' splice reg ion. Computational tools suggest a possible impact to splicing. However, this in formation is not predictive enough to determine out pathogenicity. In summary, t he clinical significance of the c.328+4A>C variant is uncertain. -

Autosomal recessive nonsyndromic hearing loss 18B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	20
Dann	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.50		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs535970426; hg19: chr11-17573626;