rs111033405

Positions:

• chr2-26465753-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_194248.3(OTOF):​c.4718T>C​(p.Ile1573Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,614,094 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 9.32

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 2-26465753-A-G is Pathogenic according to our data. Variant chr2-26465753-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26465753-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.4718T>C	p.Ile1573Thr	missense_variant	38/47	ENST00000272371.7
OTOF	NM_194323.3	c.2417T>C	p.Ile806Thr	missense_variant	21/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.4718T>C	p.Ile1573Thr	missense_variant	38/47	1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.2417T>C	p.Ile806Thr	missense_variant	21/29	1	NM_194323.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 33

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251476 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.0000791

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 47 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000360

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

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: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000574 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 9 Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 04, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Mar 01, 2023	The missense c.4718T>C (p.Ile1573Thr) variant in the OTOF gene has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Nonsyndromic Hearing Loss and Deafness, Type 9 (Iwasa, Yoh-Ichiro et al.,2022) . This variant is reported with the allele frequency (0.003%) in the gnomAD Exomes and novel in 1000 Genomes. It is submitted to ClinVar as Pathogenic/Likely Pathogenic. The amino acid Isoleucine at position 1573 is changed to a Threonine changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Pathogenic/ Likely Pathogenic. The variant is predicted as damaging by SIFT. The amino acid change p.Ile1573Thr in OTOF is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -

Bilateral sensorineural hearing impairment Pathogenic:1

Pathogenic, criteria provided, single submitter

research

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

-

This variant was detected in homozygosisi in na sporadic case of HL, born from a consanguineous marriage, segregsation confirmed -

Nonsyndromic genetic hearing loss Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 08, 2021

Variant summary: OTOF c.4718T>C (p.Ile1573Thr) results in a non-conservative amino acid change located in the sixth C2 domain (IPR000008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251476 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 (0.0011), allowing no conclusion about variant significance. c.4718T>C has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Nonsyndromic Hearing Loss and Deafness, Type 9 (Duman_2011, Yildirim-Baylan_2014, Sloan-Heggen_2015, Iwasa_2021). 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. One submitter has provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1573 of the OTOF protein (p.Ile1573Thr). This variant is present in population databases (rs111033405, gnomAD 0.008%). This missense change has been observed in individual(s) with deafness (PMID: 21117948, 24746455, 34536124). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48240). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on OTOF protein function. For these reasons, this variant has been classified as Pathogenic. -

Rare genetic deafness Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 02, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.8	D;D;.;D;D;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D;.;D;D;.
Sift4G	Pathogenic	0.0010	D;D;.;D;D;.
Polyphen		1.0	D;D;.;D;.;D
Vest4		0.98
MVP		0.93
MPC		0.74
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.83
gMVP		0.87

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

Other links and lift over

dbSNP: rs111033405; hg19: chr2-26688621;