rs139954767

Positions:

• chr2-26480959-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_194248.3(OTOF):​c.1630C>T​(p.Arg544Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000749 in 1,609,512 control chromosomes in the GnomAD database, including 2 homozygotes. 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. R544H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00073 (2 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 4.78

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_benign. Variant got -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.1630C>T	p.Arg544Cys	missense_variant	15/47	ENST00000272371.7
OTOF	NM_001287489.2	c.1630C>T	p.Arg544Cys	missense_variant	15/46

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.1630C>T	p.Arg544Cys	missense_variant	15/47	1	NM_194248.3	A1
OTOF	ENST00000403946.7	c.1630C>T	p.Arg544Cys	missense_variant	15/46	5		P4

Frequencies

GnomAD3 genomes AF: 0.000901 AC: 134 AN: 148666 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000993

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000667

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000201

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00174

Gnomad OTH AF: 0.000489

GnomAD3 exomes AF: 0.000769 AC: 192 AN: 249668 Hom.: 0 AF XY: 0.000797 AC XY: 108 AN XY: 135522

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.000400

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000734 AC: 1072 AN: 1460720 Hom.: 2 Cov.: 33 AF XY: 0.000778 AC XY: 565 AN XY: 726640

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00189

Gnomad4 NFE exome AF: 0.000789

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.000901 AC: 134 AN: 148792 Hom.: 0 Cov.: 33 AF XY: 0.000920 AC XY: 67 AN XY: 72800

Gnomad4 AFR AF: 0.0000990

Gnomad4 AMR AF: 0.0000666

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000201

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00105

Gnomad4 NFE AF: 0.00174

Gnomad4 OTH AF: 0.000484

Alfa AF: 0.00143 Hom.: 1

Bravo AF: 0.000635

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000801 AC: 97

EpiCase AF: 0.00115

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2022	Observed in a patient with hearing loss in published literature (Sommen et al., 2016); 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: 34426522, 27068579) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 14, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 20, 2016	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 14, 2023	Variant summary: OTOF c.1630C>T (p.Arg544Cys) results in a non-conservative amino acid change located in the Ferlin, third C2 domain (IPR037722) 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 0.00077 in 249668 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 (0.00077 vs 0.0011), allowing no conclusion about variant significance. c.1630C>T has been reported in the literature in individuals affected with Nonsyndromic Hearing Loss without evidence of cosegregation (Kothiyal_2010, Sommen_2016). 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. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variants as likely benign (n=1) or uncertain significance (n=7). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 21, 2018	The p.Arg544Cys variant in OTOF has been identified in 1 individual with autosom al recessive sensorineural hearing loss who carried a second OTOF variant of unc ertain significance; it is unclear whether these variants are in trans (Sommen 2 016). The p.Arg544Cys variant has also been identified by our laboratory in 6 in dividuals with hearing loss; however, none of these individuals carried a varian t affecting the other copy of the OTOF gene or was reported to have auditory neu ropathy typically associated with OTOF related hearing loss. This variant has be en reported in ClinVar (Variation ID: 48176). It has been identified in 0.15% (1 93/125430) of European chromosomes by the Genome Aggregation Database (gnomAD, h ttp://gnomad.broadinstitute.org); however, this frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation anal ysis suggest that the p.Arg544Cys variant may impact the protein, though this in formation is not predictive enough to determine pathogenicity. In summary, the c linical significance of the p.Arg544Cys variant is uncertain. ACMG/AMP Criteria applied: PP3, BS1_Supporting. -

Autosomal recessive nonsyndromic hearing loss 9 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 16, 2022	- -
Uncertain significance, 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, 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. -

Hearing impairment Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PP3_Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.6	D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.95
MVP		0.92
MPC		0.77
ClinPred		0.19	T
GERP RS		3.2
Varity_R		0.81
gMVP		0.72

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: rs139954767; hg19: chr2-26703827;