chr2-26465753-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_194248.3(OTOF):ā€‹c.4718T>Cā€‹(p.Ile1573Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,614,094 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 Likely pathogenic (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 33)
Exomes š‘“: 0.000032 ( 0 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

15
3
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 9.32
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.937
PP5
Variant 2-26465753-A-G is Pathogenic according to our data. Variant chr2-26465753-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26465753-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
OTOFNM_194248.3 linkuse as main transcriptc.4718T>C p.Ile1573Thr missense_variant 38/47 ENST00000272371.7 NP_919224.1
OTOFNM_194323.3 linkuse as main transcriptc.2417T>C p.Ile806Thr missense_variant 21/29 ENST00000339598.8 NP_919304.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
OTOFENST00000272371.7 linkuse as main transcriptc.4718T>C p.Ile1573Thr missense_variant 38/471 NM_194248.3 ENSP00000272371 A1Q9HC10-1
OTOFENST00000339598.8 linkuse as main transcriptc.2417T>C p.Ile806Thr missense_variant 21/291 NM_194323.3 ENSP00000344521 Q9HC10-2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152210
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000398
AC:
10
AN:
251476
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000791
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000322
AC:
47
AN:
1461884
Hom.:
0
Cov.:
32
AF XY:
0.0000303
AC XY:
22
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000360
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152210
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000574
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitterclinical testingClinical Genetics Laboratory, Skane University Hospital LundJan 11, 2024- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2024This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1573 of the OTOF protein (p.Ile1573Thr). This variant is present in population databases (rs111033405, gnomAD 0.008%). This missense change has been observed in individual(s) with deafness (PMID: 21117948, 24746455, 34536124). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48240). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on OTOF protein function. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingGeneDxNov 17, 2023In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20301429, 34426522, 31589614, 35114279, 36147510, 34652575, 21117948, 26445815, 34536124, 35982127, 24746455) -
Autosomal recessive nonsyndromic hearing loss 9 Pathogenic:2Other:1
Likely pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 04, 2021- -
not provided, no classification providedliterature onlyGeneReviews-- -
Likely pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGMMar 01, 2023The missense c.4718T>C (p.Ile1573Thr) variant in the OTOF gene has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Nonsyndromic Hearing Loss and Deafness, Type 9 (Iwasa, Yoh-Ichiro et al.,2022) . This variant is reported with the allele frequency (0.003%) in the gnomAD Exomes and novel in 1000 Genomes. It is submitted to ClinVar as Pathogenic/Likely Pathogenic. The amino acid Isoleucine at position 1573 is changed to a Threonine changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Pathogenic/ Likely Pathogenic. The variant is predicted as damaging by SIFT. The amino acid change p.Ile1573Thr in OTOF is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -
OTOF-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesAug 13, 2024The OTOF c.4718T>C variant is predicted to result in the amino acid substitution p.Ile1573Thr. This variant was reported in the homozygous and compound heterozygous states along with a truncating variant in multiple individuals with non-syndromic hearing loss and/or auditory neuropathy (Duman et al. 2011. PubMed ID: 21117948; Yildirim-Baylan et al. 2014. PubMed ID: 24746455; Table S5, Wu et al. 2022. PubMed ID: 35982127). This variant is reported in 0.0079% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -
Bilateral sensorineural hearing impairment Pathogenic:1
Pathogenic, criteria provided, single submitterresearchLaboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo-This variant was detected in homozygosisi in na sporadic case of HL, born from a consanguineous marriage, segregsation confirmed -
Nonsyndromic genetic hearing loss Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 08, 2021Variant summary: OTOF c.4718T>C (p.Ile1573Thr) results in a non-conservative amino acid change located in the sixth C2 domain (IPR000008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251476 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss and Deafness, Type 9 (0.0011), allowing no conclusion about variant significance. c.4718T>C has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Nonsyndromic Hearing Loss and Deafness, Type 9 (Duman_2011, Yildirim-Baylan_2014, Sloan-Heggen_2015, Iwasa_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One submitter has provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -
Rare genetic deafness Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 02, 2008- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.82
.;.;.;D;.;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
D;D;D;D;D;D
M_CAP
Uncertain
0.093
D
MetaRNN
Pathogenic
0.94
D;D;D;D;D;D
MetaSVM
Pathogenic
0.81
D
MutationAssessor
Pathogenic
3.9
.;.;.;H;H;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-4.8
D;D;.;D;D;.
REVEL
Pathogenic
0.92
Sift
Uncertain
0.0010
D;D;.;D;D;.
Sift4G
Pathogenic
0.0010
D;D;.;D;D;.
Polyphen
1.0
D;D;.;D;.;D
Vest4
0.98
MVP
0.93
MPC
0.74
ClinPred
0.98
D
GERP RS
5.3
Varity_R
0.83
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs111033405; hg19: chr2-26688621; API