Variant rs199904558 details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000272371.7(OTOF):c.3706C>T(p.Arg1236Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,460,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. R1236G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

OTOF
ENST00000272371.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.263

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 links:

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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=0.27290142).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.3706C>T	p.Arg1236Cys	missense_variant	29/47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3 linkuse as main transcript	c.1465C>T	p.Arg489Cys	missense_variant	12/29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.3706C>T	p.Arg1236Cys	missense_variant	29/47	1	NM_194248.3	ENSP00000272371	A1	Q9HC10-1
OTOF	ENST00000339598.8 linkuse as main transcript	c.1465C>T	p.Arg489Cys	missense_variant	12/29	1	NM_194323.3	ENSP00000344521		Q9HC10-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249240

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135298

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1460512

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726564

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:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000825

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

.;.;.;T;.;.

Eigen

Benign

0.018

Eigen_PC

Benign

-0.064

FATHMM_MKL

Benign

0.42

LIST_S2

Uncertain

0.90

D;D;D;D;D;D

M_CAP

Uncertain

0.094

MetaRNN

Benign

0.27

T;T;T;T;T;T

MetaSVM

Uncertain

-0.052

MutationAssessor

Benign

0.55

.;.;.;N;N;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.0

D;D;.;D;D;.

REVEL

Uncertain

0.38

Sift

Benign

0.087

T;T;.;D;D;.

Sift4G

Uncertain

0.015

D;D;.;D;D;.

Polyphen

0.99

D;D;.;P;.;D

Vest4

0.28

MVP

0.86

MPC

0.35

ClinPred

0.71

GERP RS

3.7

Varity_R

0.19

gMVP

0.40

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over