Genetic Variant NM_144672.4:c.2222G>C (chr16-21730851-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_144672.4(OTOA):c.2222G>C(p.Trp741Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

OTOA
NM_144672.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.55

Publications

0 publications found

Variant links:

Genes affected

OTOA (HGNC:16378): (otoancorin) The protein encoded by this gene is specifically expressed in the inner ear, and is located at the interface between the apical surface of the inner ear sensory epithelia and their overlying acellular gels. It is prposed that this protein is involved in the attachment of the inner ear acellular gels to the apical surface of the underlying nonsensory cells. Mutations in this gene are associated with autosomal recessive deafness type 22 (DFNB22). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

OTOA Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 22
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

OTOA links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144672.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTOA	NM_144672.4	MANE Select	c.2222G>C	p.Trp741Ser	missense	Exon 21 of 29	NP_653273.3
OTOA	NM_001161683.2		c.1985G>C	p.Trp662Ser	missense	Exon 16 of 24	NP_001155155.1
OTOA	NM_170664.3		c.1250G>C	p.Trp417Ser	missense	Exon 11 of 19	NP_733764.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTOA	ENST00000646100.2	MANE Select	c.2222G>C	p.Trp741Ser	missense	Exon 21 of 29	ENSP00000496564.2
OTOA	ENST00000388958.8	TSL:1	c.2222G>C	p.Trp741Ser	missense	Exon 20 of 28	ENSP00000373610.3
OTOA	ENST00000286149.8	TSL:5	c.2264G>C	p.Trp755Ser	missense	Exon 20 of 28	ENSP00000286149.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 22, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Trp741Ser variant in OTOA has not been reported in individuals with hearing loss or in large population studies. Computational prediction tools and conserva tion analysis suggest that this variant may impact the protein, though this info rmation is not predictive enough to determine pathogenicity. In summary, the cli nical significance of this variant is uncertain.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.41

MutationAssessor

Uncertain

2.9

PhyloP100

5.6

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-9.9

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.90

MutPred

0.79

Gain of disorder (P = 0.0014)

MVP

0.96

MPC

0.89

ClinPred

1.0

GERP RS

4.1

Varity_R

0.88

gMVP

0.87

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over