dbSNP rs56332208: OTOF:p.Arg33Leu (chr2-26537756-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_194248.3(OTOF):c.98G>T(p.Arg33Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,402,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R33W) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.97

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.98G>T	p.Arg33Leu	missense_variant	Exon 2 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2 link	c.98G>T	p.Arg33Leu	missense_variant	Exon 2 of 46		NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 link	c.98G>T	p.Arg33Leu	missense_variant	Exon 2 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000403946.7 link	c.98G>T	p.Arg33Leu	missense_variant	Exon 2 of 46	5		ENSP00000385255.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1402418

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

692064

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31724

American (AMR)

AF:

0.00

AC:

AN:

36414

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25230

East Asian (EAS)

AF:

0.00

AC:

AN:

36042

South Asian (SAS)

AF:

0.00

AC:

AN:

79406

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49510

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1080270

Other (OTH)

AF:

0.00

AC:

AN:

58122

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

T;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.062

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Uncertain

-0.0029

MutationAssessor

Uncertain

2.4

M;M

PhyloP100

4.0

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.9

N;N

REVEL

Uncertain

0.48

Sift

Uncertain

0.010

D;D

Sift4G

Uncertain

0.025

D;D

Polyphen

0.99

D;.

Vest4

0.79

MutPred

0.52

Loss of MoRF binding (P = 0.0185);Loss of MoRF binding (P = 0.0185);

MVP

0.92

MPC

0.73

ClinPred

1.0

GERP RS

4.8

Varity_R

0.35

gMVP

0.59

Mutation Taster

=89/11

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over