rs397515605

Positions:

chr2-26462177-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_194248.3(OTOF):c.5197G>A(p.Glu1733Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,852 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 (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic no assertion criteria provided P:2O:1

Conservation

PhyloP100: 7.83

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a domain C2 7 (size 151) in uniprot entity OTOF_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_194248.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.917

PP5

Variant 2-26462177-C-T is Pathogenic according to our data. Variant chr2-26462177-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65808.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-26462177-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.5197G>A	p.Glu1733Lys	missense_variant	42/47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 link	c.2896G>A	p.Glu966Lys	missense_variant	25/29	ENST00000339598.8	NP_919304.1	Q9HC10-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 link	c.5197G>A	p.Glu1733Lys	missense_variant	42/47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 link	c.2896G>A	p.Glu966Lys	missense_variant	25/29	1	NM_194323.3	ENSP00000344521.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152144

Hom.:

Cov.:

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251326

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461708

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74318

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Auditory neuropathy spectrum disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Otolaryngology, Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University

May 29, 2020

- -

Hearing loss, autosomal recessive

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

Autosomal recessive nonsyndromic hearing loss 9

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.68

.;.;.;D;.;.

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.92

D;D;D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

3.4

.;.;.;M;M;.

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.8

D;D;.;D;D;.

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0020

D;D;.;D;D;.

Sift4G

Uncertain

0.0040

D;D;.;D;D;.

Polyphen

1.0

D;D;.;D;.;D

Vest4

0.87

MutPred

0.79

.;.;.;Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);.;

MVP

0.96

MPC

0.70

ClinPred

1.0

GERP RS

5.1

Varity_R

0.73

gMVP

0.92

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over