rs734640

Variant names:

• chr11-17591801-A-G
• rs734640
• NM_001292063.2:c.3006+213A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001292063.2(OTOG):​c.3006+213A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.34 in 152,054 control chromosomes in the GnomAD database, including 8,952 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.34 (8952 hom., cov: 32)
• Consequence: OTOG NM_001292063.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.44
• Publications: 1 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 11-17591801-A-G is Benign according to our data. Variant chr11-17591801-A-G is described in ClinVar as Benign. ClinVar VariationId is 1221300.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.3006+213A>G		intron_variant	Intron 25 of 55	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.3042+213A>G		intron_variant	Intron 24 of 54		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.3006+213A>G		intron_variant	Intron 25 of 55	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.3042+213A>G		intron_variant	Intron 24 of 54	5		ENSP00000382323.2
OTOG	ENST00000342528.2	n.372-1392A>G		intron_variant	Intron 2 of 21	2

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51623 AN: 151936 Hom.: 8941 Cov.: 32

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.449

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.326

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.332

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.340 AC: 51665 AN: 152054 Hom.: 8952 Cov.: 32 AF XY: 0.334 AC XY: 24818 AN XY: 74308

African (AFR) AF: 0.376 AC: 15581 AN: 41438

American (AMR) AF: 0.251 AC: 3843 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.326 AC: 1132 AN: 3470

East Asian (EAS) AF: 0.305 AC: 1579 AN: 5182

South Asian (SAS) AF: 0.297 AC: 1428 AN: 4808

European-Finnish (FIN) AF: 0.289 AC: 3058 AN: 10572

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.351 AC: 23855 AN: 67982

Other (OTH) AF: 0.329 AC: 693 AN: 2108

Alfa AF: 0.326 Hom.: 1460

Bravo AF: 0.339

Asia WGS AF: 0.303 AC: 1054 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.0010
DANN	Benign	0.58
PhyloP100		-4.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs734640; hg19: chr11-17613348;