rs111033329

Variant names:

• chr2-26461006-C-T
• rs111033329
• NM_194248.3:c.5558G>A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_194248.3(OTOF):​c.5558G>A​(p.Arg1853Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0094 in 1,383,832 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0067 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0097 (60 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 4.99

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 Benign. Variant got -11 ACMG points.

• PM1: In a domain C2 7 (size 151) in uniprot entity OTOF_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_194248.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.010482699).
• BP6: Variant 2-26461006-C-T is Benign according to our data. Variant chr2-26461006-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48262.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00669 (946/141400) while in subpopulation NFE AF= 0.0101 (658/65122). AF 95% confidence interval is 0.00946. There are 4 homozygotes in gnomad4. There are 461 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.5558G>A	p.Arg1853Gln	missense_variant	Exon 44 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.3257G>A	p.Arg1086Gln	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.5558G>A	p.Arg1853Gln	missense_variant	Exon 44 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.3257G>A	p.Arg1086Gln	missense_variant	Exon 27 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.00669 AC: 946 AN: 141304 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.0148

Gnomad AMR AF: 0.00186

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0213

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00349

GnomAD3 exomes AF: 0.00720 AC: 1805 AN: 250616 Hom.: 9 AF XY: 0.00717 AC XY: 972 AN XY: 135602

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0177

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.00768

GnomAD4 exome AF: 0.00971 AC: 12062 AN: 1242432 Hom.: 60 Cov.: 36 AF XY: 0.00945 AC XY: 5820 AN XY: 616088

Gnomad4 AFR exome AF: 0.00174

Gnomad4 AMR exome AF: 0.00205

Gnomad4 ASJ exome AF: 0.000566

Gnomad4 EAS exome AF: 0.0000526

Gnomad4 SAS exome AF: 0.0000712

Gnomad4 FIN exome AF: 0.0280

Gnomad4 NFE exome AF: 0.0108

Gnomad4 OTH exome AF: 0.00888

GnomAD4 genome AF: 0.00669 AC: 946 AN: 141400 Hom.: 4 Cov.: 31 AF XY: 0.00674 AC XY: 461 AN XY: 68376

Gnomad4 AFR AF: 0.00146

Gnomad4 AMR AF: 0.00186

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0213

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.00345

Alfa AF: 0.00856 Hom.: 9

Bravo AF: 0.00496

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00860 AC: 74

ExAC AF: 0.00852 AC: 1035

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.00747

EpiControl AF: 0.00723

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Jun 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

OTOF: BS1, BS2 -

not specified Benign:2

Feb 24, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature, but it has now been identi fied in our laboratory in five individuals (5/265 or 1.9% of cases), none of who m have auditory neuropathy and three of whom have pathogenic variants in other g enes suggestive of another cause of hearing loss. In summary, the available data suggests this variant is benign. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 9 Uncertain:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	.;.;.;T;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
MetaRNN	Benign	0.010	T;T;T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.8	.;.;.;M;M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.5	D;D;.;N;N;.
REVEL	Uncertain	0.52
Sift	Benign	0.22	T;T;.;T;T;.
Sift4G	Benign	0.18	T;T;.;T;T;.
Polyphen		0.96	P;P;.;D;.;D
Vest4		0.76
MVP		0.89
MPC		0.33
ClinPred		0.041	T
GERP RS		3.9
Varity_R		0.36
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs111033329; hg19: chr2-26683874; COSMIC: COSV55507669; COSMIC: COSV55507669;