2-26460203-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM5PP5_Very_Strong

The NM_194248.3(OTOF):c.5816G>A(p.Arg1939Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,600,492 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1939W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

OTOF
NM_194248.3 missense, splice_region

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:1O:1

Conservation

PhyloP100: 2.63

Publications

36 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: Pathogenic. The variant received 10 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-26460204-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 65813.

PP5

Variant 2-26460203-C-T is Pathogenic according to our data. Variant chr2-26460203-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194248.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTOF	NM_194248.3	MANE Select	c.5816G>A	p.Arg1939Gln	missense splice_region	Exon 46 of 47	NP_919224.1
OTOF	NM_194323.3	MANE Plus Clinical	c.3512+444G>A		intron	N/A	NP_919304.1
OTOF	NM_194322.3		c.3746G>A	p.Arg1249Gln	missense splice_region	Exon 28 of 29	NP_919303.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTOF	ENST00000272371.7	TSL:1 MANE Select	c.5816G>A	p.Arg1939Gln	missense splice_region	Exon 46 of 47	ENSP00000272371.2
OTOF	ENST00000402415.8	TSL:1	c.3575G>A	p.Arg1192Gln	missense splice_region	Exon 28 of 29	ENSP00000383906.4
OTOF	ENST00000338581.10	TSL:1	c.3515G>A	p.Arg1172Gln	missense splice_region	Exon 29 of 30	ENSP00000345137.6

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000772

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

GnomAD2 exomes

AF:

0.0000612

AC:

AN:

228634

AF XY:

0.0000488

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000124

Gnomad ASJ exome

AF:

0.000103

Gnomad EAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000193

AC:

AN:

1448342

Hom.:

Cov.:

AF XY:

0.0000167

AC XY:

AN XY:

719068

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33248

American (AMR)

AF:

0.000116

AC:

AN:

43040

Ashkenazi Jewish (ASJ)

AF:

0.0000386

AC:

AN:

25914

East Asian (EAS)

AF:

0.000203

AC:

AN:

39326

South Asian (SAS)

AF:

0.00

AC:

AN:

84026

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4290

European-Non Finnish (NFE)

AF:

0.00000814

AC:

AN:

1106120

Other (OTH)

AF:

0.0000835

AC:

AN:

59864

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41510

American (AMR)

AF:

0.000131

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000774

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 9

Pathogenic:2Uncertain:1Other:1

Oct 21, 2014

Baylor Genetics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Our laboratory reported three molecular diagnoses in OTOF (NM_004802.3, c.3515G>A), SLC12A6 (NM_001042494.1, c.73dup) and USH2A (NM_206933.2, c.13709G>A and c.5858C>G in trans), in one individual with reported features of congenital deafness, autism, delayed speech, macrocephaly, and skin anomalies that include hyperpigmented areas, excessively stretchy skin, poor wound healing, and keloids. Heterozygotes for this variant would be expected to be asymptomatic carriers.

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For recessive disorders, detected in trans with a pathogenic variant.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).

Dec 23, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:2

Jun 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1939 of the OTOF protein (p.Arg1939Gln). This variant is present in population databases (rs80356605, gnomAD 0.07%). This missense change has been observed in individual(s) with auditory neuropathy spectrum disorder and/or deafness (PMID: 23562982, 34536124). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Japanese ancestry (PMID: 22575033, 34424407, 34536124). This variant is also known as c.3515G>A (p.Arg1172Gln). ClinVar contains an entry for this variant (Variation ID: 6136). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant disrupts the p.Arg1939 amino acid residue in OTOF. Other variant(s) that disrupt this residue have been observed in individuals with OTOF-related conditions (PMID: 34536124), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Aug 14, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PM2_supporting

Auditory neuropathy, autosomal recessive, 1

Pathogenic:1

Jan 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

Eigen

Uncertain

0.39

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.77

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.45

MetaSVM

Uncertain

0.71

MutationAssessor

Pathogenic

3.6

PhyloP100

2.6

PrimateAI

Benign

0.23

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.38

MVP

0.91

MPC

0.64

ClinPred

0.97

GERP RS

2.3

Varity_R

0.88

gMVP

0.93

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over