Genetic Variant OTOF:p.Ala1163Glu (chr2-26473488-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_194248.3(OTOF):c.3488C>A(p.Ala1163Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1163T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.93

Publications

0 publications found

Variant links:

Genes affected

OTOF (HGNC:8515): (otoferlin) Mutations in this gene are a cause of neurosensory nonsyndromic recessive deafness, DFNB9. The short form of the encoded protein has 3 C2 domains, a single carboxy-terminal transmembrane domain found also in the C. elegans spermatogenesis factor FER-1 and human dysferlin, while the long form has 6 C2 domains. The homology suggests that this protein may be involved in vesicle membrane fusion. Several transcript variants encoding multiple isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OTOF Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 9
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

OTOF links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194248.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTOF	NM_194248.3	MANE Select	c.3488C>A	p.Ala1163Glu	missense	Exon 28 of 47	NP_919224.1
OTOF	NM_194323.3	MANE Plus Clinical	c.1247C>A	p.Ala416Glu	missense	Exon 11 of 29	NP_919304.1
OTOF	NM_001287489.2		c.3488C>A	p.Ala1163Glu	missense	Exon 28 of 46	NP_001274418.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTOF	ENST00000272371.7	TSL:1 MANE Select	c.3488C>A	p.Ala1163Glu	missense	Exon 28 of 47	ENSP00000272371.2
OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.1247C>A	p.Ala416Glu	missense	Exon 11 of 29	ENSP00000344521.3
OTOF	ENST00000402415.8	TSL:1	c.1247C>A	p.Ala416Glu	missense	Exon 10 of 29	ENSP00000383906.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250524

AF XY:

0.00

show subpopulations

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:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

M_CAP

Benign

0.040

MetaRNN

Uncertain

0.74

MetaSVM

Benign

-0.53

MutationAssessor

Pathogenic

2.9

PhyloP100

9.9

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.56

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.89

MutPred

0.66

Gain of disorder (P = 0.0179)

MVP

0.64

MPC

0.71

ClinPred

1.0

GERP RS

5.4

PromoterAI

0.027

Neutral

(source)

Varity_R

0.84

gMVP

0.85

Mutation Taster

=28/72

disease causing

(source)

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

Computational scores

Splicing

Publications

Other links and lift over