11-17553438-G-T

Variant names:

• chr11-17553438-G-T
• rs1554967816
• NM_001292063.2:c.459G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001292063.2(OTOG):​c.459G>T​(p.Gly153Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000681 in 1,322,510 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.132
• 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 -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 11-17553438-G-T is Benign according to our data. Variant chr11-17553438-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 505189.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.132 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001292063.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	NM_001292063.2	MANE Select	c.459G>T	p.Gly153Gly	synonymous	Exon 6 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.495G>T	p.Gly165Gly	synonymous	Exon 5 of 55	NP_001264198.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.459G>T	p.Gly153Gly	synonymous	Exon 6 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.495G>T	p.Gly165Gly	synonymous	Exon 5 of 55	ENSP00000382323.2
	OTOG	ENST00000428619.1	TSL:3	c.276G>T	p.Gly92Gly	synonymous	Exon 4 of 4	ENSP00000399057.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000681 AC: 9 AN: 1322510 Hom.: 0 Cov.: 32 AF XY: 0.00000466 AC XY: 3 AN XY: 643964

African (AFR) AF: 0.00 AC: 0 AN: 29074

American (AMR) AF: 0.00 AC: 0 AN: 23510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20176

East Asian (EAS) AF: 0.00 AC: 0 AN: 34950

South Asian (SAS) AF: 0.00 AC: 0 AN: 66042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5330

European-Non Finnish (NFE) AF: 0.00000863 AC: 9 AN: 1043018

Other (OTH) AF: 0.00 AC: 0 AN: 54726

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Sep 04, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Gly165Gly in exon 5 of OTOG: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.5
DANN	Benign	0.72
PhyloP100		0.13

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: rs1554967816; hg19: chr11-17574985;