rs550895099

Positions:

• chr11-17576854-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_001292063.2(OTOG):​c.2562-14G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,550,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: OTOG NM_001292063.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.182

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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-17576854-G-A is Benign according to our data. Variant chr11-17576854-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.2562-14G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000399397.6
OTOG	NM_001277269.2	c.2598-14G>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.2562-14G>A		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.2598-14G>A		splice_polypyrimidine_tract_variant, intron_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152134 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000121 AC: 18 AN: 148672 Hom.: 0 AF XY: 0.000137 AC XY: 11 AN XY: 80034

Gnomad AFR exome AF: 0.000148

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.000120

Gnomad EAS exome AF: 0.0000928

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000164

Gnomad OTH exome AF: 0.000233

GnomAD4 exome AF: 0.000104 AC: 145 AN: 1398002 Hom.: 0 Cov.: 31 AF XY: 0.000104 AC XY: 72 AN XY: 689516

Gnomad4 AFR exome AF: 0.000285

Gnomad4 AMR exome AF: 0.000196

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.000112

Gnomad4 SAS exome AF: 0.0000253

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000105

Gnomad4 OTH exome AF: 0.000138

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152252 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74438

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000215 Hom.: 0

Bravo AF: 0.000189

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2015

c.2598-14G>A in intron 21 of OTOG: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 24, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.7
DANN	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs550895099; hg19: chr11-17598401;