rs766417394

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_194323.3(OTOF):​c.3667A>G​(p.Met1223Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

OTOF
NM_194323.3 missense

Scores

3
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.54
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3031101).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
OTOFNM_194323.3 linkc.3667A>G p.Met1223Val missense_variant Exon 29 of 29 ENST00000339598.8 NP_919304.1 Q9HC10-2
OTOFNM_194248.3 linkc.*172A>G 3_prime_UTR_variant Exon 47 of 47 ENST00000272371.7 NP_919224.1 Q9HC10-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
OTOFENST00000339598.8 linkc.3667A>G p.Met1223Val missense_variant Exon 29 of 29 1 NM_194323.3 ENSP00000344521.3 Q9HC10-2
OTOFENST00000272371 linkc.*172A>G 3_prime_UTR_variant Exon 47 of 47 1 NM_194248.3 ENSP00000272371.2 Q9HC10-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152114
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.0000279
AC:
7
AN:
250958
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135614
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:
0.0000529
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000192
AC:
28
AN:
1461622
Hom.:
0
Cov.:
31
AF XY:
0.0000165
AC XY:
12
AN XY:
727064
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000234
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152114
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74304
show subpopulations
Gnomad4 AFR
AF:
0.0000242
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:
0.0000579
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000237

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Feb 28, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
18
DANN
Benign
0.97
Eigen
Benign
-0.044
Eigen_PC
Benign
0.11
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.80
T;T
M_CAP
Uncertain
0.23
D
MetaRNN
Benign
0.30
T;T
MetaSVM
Benign
-0.67
T
PROVEAN
Benign
-0.12
N;N
REVEL
Benign
0.20
Sift
Benign
0.067
T;T
Sift4G
Uncertain
0.053
T;T
Polyphen
0.0060
B;.
Vest4
0.45
MVP
0.77
ClinPred
0.22
T
GERP RS
4.8

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: rs766417394; hg19: chr2-26680934; API