chr2-26465007-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3BS1_Supporting

The NM_194248.3(OTOF):c.4822G>T(p.Asp1608Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000065 in 1,492,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1608E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.86

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.795

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000694 (93/1339874) while in subpopulation SAS AF = 0.00131 (85/65082). AF 95% confidence interval is 0.00108. There are 0 homozygotes in GnomAdExome4. There are 57 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.4822G>T	p.Asp1608Tyr	missense_variant	Exon 39 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 link	c.2521G>T	p.Asp841Tyr	missense_variant	Exon 22 of 29	ENST00000339598.8	NP_919304.1	Q9HC10-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 link	c.4822G>T	p.Asp1608Tyr	missense_variant	Exon 39 of 47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 link	c.2521G>T	p.Asp841Tyr	missense_variant	Exon 22 of 29	1	NM_194323.3	ENSP00000344521.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000102

AC:

AN:

177074

AF XY:

0.000106

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:

0.0000120

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000694

AC:

AN:

1339874

Hom.:

Cov.:

AF XY:

0.0000870

AC XY:

AN XY:

655138

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28640

American (AMR)

AF:

0.00

AC:

AN:

33940

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20592

East Asian (EAS)

AF:

0.00

AC:

AN:

35996

South Asian (SAS)

AF:

0.00131

AC:

AN:

65082

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49706

Middle Eastern (MID)

AF:

0.000190

AC:

AN:

5250

European-Non Finnish (NFE)

AF:

0.00000191

AC:

AN:

1045714

Other (OTH)

AF:

0.0000910

AC:

AN:

54954

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41532

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000829

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67980

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00149

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.000124

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Feb 25, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Sep 24, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid with tyrosine at codon 1608 of the OTOF protein (p.Asp1608Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs111033425, ExAC 0.1%). This variant has not been reported in the literature in individuals with OTOF-related conditions. ClinVar contains an entry for this variant (Variation ID: 48241). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

May 26, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

May 06, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.4822G>T (p.D1608Y) alteration is located in exon 39 (coding exon 39) of the OTOF gene. This alteration results from a G to T substitution at nucleotide position 4822, causing the aspartic acid (D) at amino acid position 1608 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

.;.;.;D;.;.

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

D;D;D;D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.80

D;D;D;D;D;D

MetaSVM

Uncertain

0.43

MutationAssessor

Pathogenic

3.5

.;.;.;H;H;.

PhyloP100

7.9

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-8.8

D;D;.;D;D;.

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;D;.;D;D;.

Sift4G

Pathogenic

0.0

D;D;.;D;D;.

Polyphen

1.0

D;D;.;D;.;D

Vest4

0.76

MutPred

0.85

.;.;.;Gain of MoRF binding (P = 0.034);Gain of MoRF binding (P = 0.034);.;

MVP

0.90

MPC

0.73

ClinPred

0.80

GERP RS

4.9

Varity_R

0.92

gMVP

0.88

Mutation Taster

=15/85

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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chr2-26465007-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over