rs906307749

Variant names:

• chr11-17586587-T-G
• rs906307749
• NM_001292063.2:c.2867+6T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001292063.2(OTOG):​c.2867+6T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00029 in 1,364,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: OTOG NM_001292063.2 splice_region, intron
• Scores: Splicing: ADA: 0.3786
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.52
• Publications: 0 publications found

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]

OTOG Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 18B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.2867+6T>G		splice_region_variant, intron_variant	Intron 24 of 55	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.2903+6T>G		splice_region_variant, intron_variant	Intron 23 of 54		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.2867+6T>G		splice_region_variant, intron_variant	Intron 24 of 55	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.2903+6T>G		splice_region_variant, intron_variant	Intron 23 of 54	5		ENSP00000382323.2
OTOG	ENST00000342528.2	n.371+6T>G		splice_region_variant, intron_variant	Intron 2 of 21	2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152082 Hom.: 0 Cov.: 33

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: 0.000221

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000505 AC: 2 AN: 39624 AF XY: 0.0000496

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000138

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000311 AC: 377 AN: 1212284 Hom.: 0 Cov.: 26 AF XY: 0.000299 AC XY: 175 AN XY: 586128

African (AFR) AF: 0.00 AC: 0 AN: 24912

American (AMR) AF: 0.00 AC: 0 AN: 13694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17534

East Asian (EAS) AF: 0.00 AC: 0 AN: 28212

South Asian (SAS) AF: 0.00 AC: 0 AN: 47900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5022

European-Non Finnish (NFE) AF: 0.000381 AC: 374 AN: 981794

Other (OTH) AF: 0.0000603 AC: 3 AN: 49750

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152082 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74288

African (AFR) AF: 0.0000242 AC: 1 AN: 41376

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000126 Hom.: 0

Bravo AF: 0.000144

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 09, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2903+6T>G variant in OTOG has not been previously reported in individuals with hearing loss. Data from large population studies are insufficient to assess the frequency of this variant in the general population. This variant is locate d in the 5' splice region. Computational tools suggest an impact to splicing; ho wever, this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the c.2903+6T>G variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Benign	0.94
PhyloP100		1.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.38
dbscSNV1_RF	Benign	0.28
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.38		Position offset: -6

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

Other links and lift over

dbSNP: rs906307749; hg19: chr11-17608134;