chr2-26461897-C-A

Position:

• chr2-26461897-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PM1 PM2 PM5 PP3 PP5 BP4

The ENST00000272371.7(OTOF):​c.5332G>T​(p.Val1778Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1778I) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: OTOF ENST00000272371.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:3
• Conservation: PhyloP100: 7.86

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000272371.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-26461897-C-T is described in Lovd as [Pathogenic].
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PrimateAI, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 2-26461897-C-A is Pathogenic according to our data. Variant chr2-26461897-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48258.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=3}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2941755). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.5332G>T	p.Val1778Phe	missense_variant	43/47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.3031G>T	p.Val1011Phe	missense_variant	26/29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.5332G>T	p.Val1778Phe	missense_variant	43/47	1	NM_194248.3	ENSP00000272371	A1
OTOF	ENST00000339598.8	c.3031G>T	p.Val1011Phe	missense_variant	26/29	1	NM_194323.3	ENSP00000344521

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000227 AC: 57 AN: 251478 Hom.: 0 AF XY: 0.000213 AC XY: 29 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00506

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000116 AC: 170 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.000105 AC XY: 76 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00509

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74306

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000346 Hom.: 0

Bravo AF: 0.000159

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000988 AC: 12

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nonsyndromic genetic hearing loss Pathogenic:3

Likely pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_194248.2:c.5332G>T in the OTOF gene has an allele frequency of 0.005 in Ashkenazi Jewish subpopulation in the gnomAD database. This c.5332G>T (p.Val1778Phe) variant has been reported in one study in which it was found in a homozygous state in four siblings affected with an autosomal recessive form of nonsyndromic sensorineural hearing loss, and in a heterozygous state in both parents and four unaffected siblings (PMID: 27621663). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PP1_Strong, PP3, PP4, PM3_Supporting. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 29, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 04, 2024	Variant summary: OTOF c.5332G>T (p.Val1778Phe) results in a non-conservative amino acid change located in the C2 domain 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 0.00023 in 251478 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 (0.00023 vs 0.0011). However, the frequency of the variant in the Ashkenazi Jewish population suggests a high carrier frequency (0.0051; gnomad). c.5332G>T has been reported in the literature in multiple individuals affected with Nonsyndromic Hearing Loss And Deafness including four siblings from a large Ashkenazi Jewish family (Fedick_2016) and a patient reported to be compound heterozygous for the variant (reported from Fedick_2016 as a personal communication with the author). 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: 27621663, 20146813). ClinVar contains an entry for this variant (Variation ID: 48258). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 31, 2017	The p.Val1778Phe variant (rs111033330) has been previously reported in association with auditory neuropathy in an Ashkenazi Jewish family (Fedick 2016). Fedick et al reported 4 siblings homozygous for the p.Val1778Phe variant with highly variable degrees of hearing loss (mild to moderately -severe) and auditory brainstem response testing consistent with auditory neuropathy/dys-synchrony. This variant has been reported to ClinVar (Variation ID: 48258) and according to information provided by Fedick et al the entry from Partners HealthCare represents a 2nd Jewish family with the p.Val1778Phe variant in trans with a known pathogenic variant, but that information is not available on ClinVar. The p.Val1778Phe variant is predicted to be more frequent in Ashkenazi Jewish individuals than in other populations with an estimated frequency of 0.4 - 1.27 percent (gnomAD, and Fedick 2016). Altogether, there is not enough evidence to classify the p.Val1778Phe variant with certainty. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1778 of the OTOF protein (p.Val1778Phe). This variant is present in population databases (rs111033330, gnomAD 0.5%). This missense change has been observed in individual(s) with nonsyndromic deafness (PMID: 27621663). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48258). 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27621663) -

Autosomal recessive nonsyndromic hearing loss 9 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 19, 2018	The OTOF c.5332G>T (p.Val1778Phe) variant has been reported in one study in which it was found in a homozygous state in four siblings affected with an autosomal recessive form of nonsyndromic sensorineural hearing loss, and in a heterozygous state in both parents and four unaffected siblings (Fedick et al. 2016). The affected individuals exhibited a variable degree of hearing loss from mild to moderately severe. The p.Val1778Phe variant was found in 13 of 1021 Ashkenazi Jewish controls and determined to have a carrier frequency of 1.27%, suggesting a founder variant, and is reported at a frequency of 0.004827 in the Ashkenazi Jewish population of the Genome Aggregation Database. The valine residue at this position is in a highly conserved region (Fedick et al. 2016). A second variant has been reported in a heterozygous state in one Japanese individual affected with hearing loss, at the same nucleotide position (c.5332G>A) resulting in substitution of the valine residue with isoleucine (Iwasa et al. 2013). Based on the evidence, the p.Val1778Phe variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 08, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;.;.;D;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.29	T;T;T;T;T;T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.9	.;.;.;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.2	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		0.98	D;D;.;D;.;D
Vest4		0.90
MVP		0.96
MPC		0.62
ClinPred		0.83	D
GERP RS		5.0
Varity_R		0.71
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs111033330; hg19: chr2-26684765;