rs61740776

Positions:

• chr2-26473257-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_194248.3(OTOF):​c.3608A>G​(p.Asn1203Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,613,348 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (54 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (51 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.49

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005012989).
• BP6: Variant 2-26473257-T-C is Benign according to our data. Variant chr2-26473257-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 48219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.3608A>G	p.Asn1203Ser	missense_variant	29/47	ENST00000272371.7
OTOF	NM_194323.3	c.1367A>G	p.Asn456Ser	missense_variant	12/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.3608A>G	p.Asn1203Ser	missense_variant	29/47	1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.1367A>G	p.Asn456Ser	missense_variant	12/29	1	NM_194323.3

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2374 AN: 152042 Hom.: 53 Cov.: 33

Gnomad AFR AF: 0.0551

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00391 AC: 979 AN: 250338 Hom.: 13 AF XY: 0.00293 AC XY: 397 AN XY: 135660

Gnomad AFR exome AF: 0.0528

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00156 AC: 2285 AN: 1461188 Hom.: 51 Cov.: 33 AF XY: 0.00134 AC XY: 976 AN XY: 726892

Gnomad4 AFR exome AF: 0.0556

Gnomad4 AMR exome AF: 0.00280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000423

Gnomad4 OTH exome AF: 0.00364

GnomAD4 genome AF: 0.0156 AC: 2380 AN: 152160 Hom.: 54 Cov.: 33 AF XY: 0.0149 AC XY: 1107 AN XY: 74382

Gnomad4 AFR AF: 0.0551

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00355 Hom.: 11

Bravo AF: 0.0170

ESP6500AA AF: 0.0561 AC: 247

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00469 AC: 569

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 26, 2011	Asn1203Ser in exon 29 of OTOF: This variant is not expected to have clinical sig nificance due to a frequency of 5.9% (7/118) in Black controls (rs61740776). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 14, 2018	- -

Autosomal recessive nonsyndromic hearing loss 9 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 08, 2021	- -

OTOF-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 13, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Bilateral sensorineural hearing impairment Benign:1

Benign, criteria provided, single submitter

research

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

-

clinical significance unknown since this variant was found in single heterozygosis and a likely pathogenic heterozygous variant in FGFR2 was detected, which is more probably related to the phenotype -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.60
CADD	Uncertain	24
DANN	Benign	0.97
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.082
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D
MetaRNN	Benign	0.0050	T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.43	N;N;.;N;N;.
REVEL	Benign	0.16
Sift	Benign	1.0	T;T;.;T;T;.
Sift4G	Benign	1.0	T;T;.;T;T;.
Polyphen		0.033	B;B;.;P;.;P
Vest4		0.45
MVP		0.43
MPC		0.59
ClinPred		0.035	T
GERP RS		4.9
Varity_R		0.13
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61740776; hg19: chr2-26696125;