2-26477473-GC-G

Position:

chr2-26477473-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_194248.3(OTOF):c.2348del(p.Gly783AlafsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,603,742 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

OTOF
NM_194248.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 2.21

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-26477473-GC-G is Pathogenic according to our data. Variant chr2-26477473-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 21834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26477473-GC-G is described in Lovd as [Pathogenic]. Variant chr2-26477473-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.2348del	p.Gly783AlafsTer17	frameshift_variant	20/47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3 linkuse as main transcript	c.107del	p.Gly36AlafsTer17	frameshift_variant	3/29	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.2348del	p.Gly783AlafsTer17	frameshift_variant	20/47	1	NM_194248.3	ENSP00000272371	A1	Q9HC10-1
OTOF	ENST00000339598.8 linkuse as main transcript	c.107del	p.Gly36AlafsTer17	frameshift_variant	3/29	1	NM_194323.3	ENSP00000344521		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000390

AC:

AN:

230852

Hom.:

AF XY:

0.0000240

AC XY:

AN XY:

124958

show subpopulations

Gnomad AFR exome

AF:

0.000141

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:

0.0000675

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000105

AC:

153

AN:

1451656

Hom.:

Cov.:

AF XY:

0.0000915

AC XY:

AN XY:

720996

show subpopulations

Gnomad4 AFR exome

AF:

0.0000899

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000154

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000126

Gnomad4 OTH exome

AF:

0.000100

GnomAD4 genome

AF:

0.000112

AC:

AN:

152086

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.000110

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 9

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Apr 22, 2022	This sequence change is a deletion of 1 bp in exon 20 (of 46) of OTOF that is predicted to create a premature termination codon at position 799, p.(Gly783Alafs*17), which is expected to result in an absent or disrupted protein product. Loss of function is an established mechanism for disease for this gene. The variant is present in a large population cohort at a frequency of 0.005% (rs80356591, 12/262,222 alleles, 0 homozygotes in gnomAD v2.1), with a frequency of 0.02% in the African subpopulation (4/22,908 alleles, 0 homozygotes). The variant has been identified compound heterozygous with a second pathogenic allele in at least two individuals with non-syndromic auditory neuropathy (PMID: 16371502, 19461658). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_Strong. -

Bilateral sensorineural hearing impairment

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Laboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo

in compound heterozygosis with another frameshift variant, both likely pathogenic in patient with auditory neuropathy -

Nonsyndromic genetic hearing loss

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 11, 2023

Variant summary: OTOF c.2348delG (p.Gly783AlafsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic within ClinVar (e.g. c.2485C>T [p.Gln829Ter], c.2977_2978del [p.Gln994fs]). The variant allele was found at a frequency of 4.6e-05 in 262222 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 (4.6e-05 vs 0.0011), allowing no conclusion about variant significance. c.2348delG has been reported in the literature as a biallelic genotype in individuals affected with Nonsyndromic Hearing Loss And Deafness (e.g. Varga_2006, Romanos_2009, Rodriguez-Ballesteros_2008, Baux_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: all three classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

This sequence change creates a premature translational stop signal (p.Gly783Alafs*17) in the OTOF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOF are known to be pathogenic (PMID: 18381613, 19250381, 22575033). This variant is present in population databases (rs80356591, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of OTOF-related conditions (PMID: 16371502, 31980526). ClinVar contains an entry for this variant (Variation ID: 21834). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 26, 2015

The p.Gly783fs variant in OTOF has been reported in 2 siblings with auditory neu ropathy (Varga 2006) and has been identified by our laboratory in 1 individual w ith congenital hearing loss. All of these individuals were compound heterozygous . Data from large population studies are insufficient to assess the frequency of this variant. The p.Gly783fs variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 783 and leads to a premature termination codon 17 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant me ets our criteria to be classified as pathogenic for hearing loss in an autosomal recessive manner (www.partners.org/personalizedmedicine/LMM) based upon its pre dicted impact on the protein. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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