11-17553374-C-T

Variant names:

• chr11-17553374-C-T
• rs766172178
• NM_001292063.2:c.395C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001292063.2(OTOG):​c.395C>T​(p.Ala132Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000229 in 1,311,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A132A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.981
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09464091).
• BP6: Variant 11-17553374-C-T is Benign according to our data. Variant chr11-17553374-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 227781.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.395C>T	p.Ala132Val	missense_variant	Exon 6 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.431C>T	p.Ala144Val	missense_variant	Exon 5 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.395C>T	p.Ala132Val	missense_variant	Exon 6 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.431C>T	p.Ala144Val	missense_variant	Exon 5 of 55	5		ENSP00000382323.2
OTOG	ENST00000428619.1	c.212C>T	p.Ala71Val	missense_variant	Exon 4 of 4	3		ENSP00000399057.2
OTOG	ENST00000498332.5	n.301C>T		non_coding_transcript_exon_variant	Exon 5 of 16	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000229 AC: 3 AN: 1311776 Hom.: 0 Cov.: 32 AF XY: 0.00000157 AC XY: 1 AN XY: 636820

African (AFR) AF: 0.00 AC: 0 AN: 28826

American (AMR) AF: 0.00 AC: 0 AN: 22856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19470

East Asian (EAS) AF: 0.00 AC: 0 AN: 34878

South Asian (SAS) AF: 0.00 AC: 0 AN: 64710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5274

European-Non Finnish (NFE) AF: 0.00000289 AC: 3 AN: 1036528

Other (OTH) AF: 0.00 AC: 0 AN: 54224

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Aug 18, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala144Val in exon 5 of OTOG: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, mouse, dolphin, killer whale and elephant have a valine (Val) at this posit ion despite high nearby amino acid conservation. In addition, computational pred iction tools do not suggest a high likelihood of impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	13
DANN	Benign	0.73
DEOGEN2	Benign	0.033	T;.;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.095	T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.0	N;.;.
PhyloP100		0.98
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.020	N;.;.
REVEL	Benign	0.036
Sift	Benign	0.48	T;.;.
Sift4G	Benign	1.0	T;T;T
Vest4		0.14
MutPred		0.60		Loss of disorder (P = 0.1918);.;.;
MVP		0.040
ClinPred		0.047	T
GERP RS		1.4
Varity_R		0.025
gMVP		0.18
Mutation Taster		=95/5	polymorphism

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: rs766172178; hg19: chr11-17574921;