rs397515608

chr2-26460997-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_194248.3(OTOF):c.5567G>A(p.Arg1856Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000515 in 1,358,022 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1856W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.90

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-26460998-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48263.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-26460997-C-T is Pathogenic according to our data. Variant chr2-26460997-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26460997-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.5567G>A	p.Arg1856Gln	missense_variant	44/47	ENST00000272371.7
OTOF	NM_194323.3	c.3266G>A	p.Arg1089Gln	missense_variant	27/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.5567G>A	p.Arg1856Gln	missense_variant	44/47	1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.3266G>A	p.Arg1089Gln	missense_variant	27/29	1	NM_194323.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250872 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135698

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000994

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: 0.00000515 AC: 7 AN: 1358022 Hom.: 0 Cov.: 36 AF XY: 0.00000445 AC XY: 3 AN XY: 674302

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000452

Gnomad4 EAS exome AF: 0.0000321

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000383

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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

Jun 20, 2020

- -

Nonsyndromic genetic hearing loss Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 01, 2023

Variant summary: OTOF c.5567G>A (p.Arg1856Gln) results in a conservative amino acid change located in the C2 domain IPR000008) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250872 control chromosomes. c.5567G>A has been reported in the literature in multiple individuals affected with Nonsyndromic Hearing Loss And Deafness (Choi_2009, Iwasa_2019, Iwasa_2013) and shown to segregate with disease. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19250381, 24053799, 31095577). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 25, 2023

ClinVar contains an entry for this variant (Variation ID: 65811). This missense change has been observed in individuals with deafness (PMID: 19250381, 31095577, 34536124). This variant is present in population databases (rs397515608, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1856 of the OTOF protein (p.Arg1856Gln). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt OTOF protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg1856 amino acid residue in OTOF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26445815, 26632695, 30482216, 32860223). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. -

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	0.88
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	35
Dann	Pathogenic	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D
MetaSVM	Uncertain	0.41	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.8	D;D;.;D;D;.
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D;D;.;D;D;.
Sift4G	Uncertain	0.0040	D;D;.;D;D;.
Polyphen		0.94	P;D;.;D;.;D
Vest4		0.93
MutPred		0.76		.;.;.;Gain of methylation at K1859 (P = 0.0637);Gain of methylation at K1859 (P = 0.0637);.;
MVP		0.90
MPC		0.36
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.63
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.89		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397515608; hg19: chr2-26683865; COSMIC: COSV55496561; COSMIC: COSV55496561;