rs147978393

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_194248.3(OTOF):​c.2075G>T​(p.Arg692Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000187 in 1,601,516 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R692Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

1
11
7

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.06
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
OTOFNM_194248.3 linkuse as main transcriptc.2075G>T p.Arg692Leu missense_variant 17/47 ENST00000272371.7
OTOFNM_001287489.2 linkuse as main transcriptc.2075G>T p.Arg692Leu missense_variant 17/46

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
OTOFENST00000272371.7 linkuse as main transcriptc.2075G>T p.Arg692Leu missense_variant 17/471 NM_194248.3 A1Q9HC10-1
OTOFENST00000403946.7 linkuse as main transcriptc.2075G>T p.Arg692Leu missense_variant 17/465 P4Q9HC10-5

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152198
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.90e-7
AC:
1
AN:
1449318
Hom.:
0
Cov.:
34
AF XY:
0.00000139
AC XY:
1
AN XY:
719962
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
9.03e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152198
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.0000482
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.080
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.47
T;.
Eigen
Benign
-0.11
Eigen_PC
Benign
0.0090
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Uncertain
0.43
T;T
MetaSVM
Benign
-0.43
T
MutationAssessor
Benign
1.6
L;L
MutationTaster
Benign
0.62
N;N
PrimateAI
Uncertain
0.58
T
PROVEAN
Uncertain
-4.4
D;D
REVEL
Uncertain
0.38
Sift
Uncertain
0.0090
D;D
Sift4G
Benign
0.064
T;T
Polyphen
0.028
B;.
Vest4
0.52
MutPred
0.43
Loss of disorder (P = 0.0457);Loss of disorder (P = 0.0457);
MVP
0.85
MPC
0.37
ClinPred
0.99
D
GERP RS
4.4
Varity_R
0.36
gMVP
0.50

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.14
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: rs147978393; hg19: chr2-26702359; API