rs148532589

Variant names:

• chr2-26477448-G-A
• rs148532589
• NM_194248.3:c.2374C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-26477448-G-A
• chr2-26477448-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_194248.3(OTOF):​c.2374C>T​(p.Arg792Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,600,288 control chromosomes in the GnomAD database, including 4 homozygotes. 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. R792Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00094 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (4 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:4
• Conservation: PhyloP100: 0.958
• Publications: 8 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.055429548).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00094 (143/152206) while in subpopulation AMR AF = 0.00157 (24/15298). AF 95% confidence interval is 0.00108. There are 0 homozygotes in GnomAd4. There are 68 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.2374C>T	p.Arg792Trp	missense_variant	Exon 20 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.133C>T	p.Arg45Trp	missense_variant	Exon 3 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.2374C>T	p.Arg792Trp	missense_variant	Exon 20 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.133C>T	p.Arg45Trp	missense_variant	Exon 3 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.000934 AC: 142 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000882 AC: 200 AN: 226676 AF XY: 0.000881

Gnomad AFR exome AF: 0.000144

Gnomad AMR exome AF: 0.000834

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000581

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.000713

GnomAD4 exome AF: 0.00104 AC: 1513 AN: 1448082 Hom.: 4 Cov.: 33 AF XY: 0.00106 AC XY: 762 AN XY: 718842

African (AFR) AF: 0.0000600 AC: 2 AN: 33312

American (AMR) AF: 0.000815 AC: 35 AN: 42968

Ashkenazi Jewish (ASJ) AF: 0.0000387 AC: 1 AN: 25818

East Asian (EAS) AF: 0.000280 AC: 11 AN: 39252

South Asian (SAS) AF: 0.000335 AC: 28 AN: 83702

European-Finnish (FIN) AF: 0.00209 AC: 107 AN: 51164

Middle Eastern (MID) AF: 0.00541 AC: 31 AN: 5726

European-Non Finnish (NFE) AF: 0.00113 AC: 1245 AN: 1106232

Other (OTH) AF: 0.000885 AC: 53 AN: 59908

GnomAD4 genome AF: 0.000940 AC: 143 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.000914 AC XY: 68 AN XY: 74430

African (AFR) AF: 0.000169 AC: 7 AN: 41516

American (AMR) AF: 0.00157 AC: 24 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5168

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00128 AC: 87 AN: 68002

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.000816

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000230 AC: 1

ESP6500EA AF: 0.00117 AC: 10

ExAC AF: 0.000815 AC: 98

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Dec 26, 2024

Laboratory of Prof. Karen Avraham, Tel Aviv University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The OTOF c.2374C>T:p.(Arg792Trp) heterozygous variant was classified as pathogenic by Deafness Variation Database based on PMID: 26969326, 30622556. It was detected together with a novel OTOF variant, possibly deleterious and not found in gnomAD, c.3863C>T:p.(Ala1288Val). -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:2

Apr 24, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg792Trp in exon 20 of OTOF: This variant is not expected to have clinical si gnificance because it has been identified in 0.4% (7/1598) of Finnish chromosome s and in 0.2% (65/28842) of European chromosomes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org; dbSNP rs148532589). -

Jan 13, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: OTOF c.2374C>T (p.Arg792Trp) results in a non-conservative amino acid change in 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 0.00088 in 226676 control chromosomes, predominantly at a frequency of 0.0013 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.16 fold of the estimated maximal expected allele frequency for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 phenotype (0.0011). c.2374C>T has been reported in the literature in individuals affected with Nonsyndromic Hearing Loss And Deafness without strong evidence for causality (e.g. Sloan-Heggen_2016, Tlili_2024). These reports do not provide unequivocal conclusions about association of the variant with Nonsyndromic Hearing Loss And Deafness, Type 9. 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: 26969326, 38844983). ClinVar contains an entry for this variant (Variation ID: 164864). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Benign:2

Jul 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26969326, 30622556) -

OTOF-related disorder Uncertain:1

Aug 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The OTOF c.2374C>T variant is predicted to result in the amino acid substitution p.Arg792Trp. This variant has been reported along with a premature termination variant and two other rare missense variants in a patient with nonsyndromic hearing loss (Table S3, reported as NM_004802:c.133C>T, Sloan-Heggen et al. 2016. PubMed ID: 26969326) and was also reported without a second potentially causative variant in another patient with hearing loss (Morgan et al. 2018. PubMed ID: 30622556). This variant is reported in 0.14% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	0.0048	T
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	.;.;.;D;.;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.055	T;T;T;T;T;T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.6	.;.;.;M;M;.
PhyloP100		0.96
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.9	D;D;.;D;D;.
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D;D;.;D;D;.
Sift4G	Pathogenic	0.0010	D;D;.;D;D;.
Polyphen		1.0	D;D;.;D;.;D
Vest4		0.84
MVP		0.93
MPC		0.55
ClinPred		0.074	T
GERP RS		0.063
Varity_R		0.74
gMVP		0.52
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs148532589; hg19: chr2-26700316;