rs397515608

Variant names:

• chr2-26460997-C-T
• rs397515608
• NM_194248.3:c.5567G>A

Variant summary

Our verdict is Pathogenic. The variant received 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
• Publications: 9 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 48263.
• PP3: Splicing predictors support a deleterious 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 65811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.5567G>A	p.Arg1856Gln	missense_variant	Exon 44 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.3266G>A	p.Arg1089Gln	missense_variant	Exon 27 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.5567G>A	p.Arg1856Gln	missense_variant	Exon 44 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.3266G>A	p.Arg1089Gln	missense_variant	Exon 27 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250872 AF XY: 0.00000737

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 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

African (AFR) AF: 0.00 AC: 0 AN: 30338

American (AMR) AF: 0.00 AC: 0 AN: 41440

Ashkenazi Jewish (ASJ) AF: 0.0000452 AC: 1 AN: 22114

East Asian (EAS) AF: 0.0000321 AC: 1 AN: 31164

South Asian (SAS) AF: 0.00 AC: 0 AN: 85332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45010

Middle Eastern (MID) AF: 0.000191 AC: 1 AN: 5240

European-Non Finnish (NFE) AF: 0.00000383 AC: 4 AN: 1044126

Other (OTH) AF: 0.00 AC: 0 AN: 53258

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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

Jun 20, 2020

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nonsyndromic genetic hearing loss Pathogenic:1

Sep 01, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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. 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). -

Autosomal recessive nonsyndromic hearing loss 9 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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
DEOGEN2	Uncertain	0.50	.;.;.;T;.;.
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
MutationAssessor	Uncertain	2.7	.;.;.;M;M;.
PhyloP100		7.9
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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

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