rs1879761

Positions:

• chr2-26527901-G-A

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.158C>T​(p.Ala53Val) variant causes a missense change. The variant allele was found at a frequency of 0.0227 in 1,613,822 control chromosomes in the GnomAD database, including 4,689 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 0.032 (529 hom., cov: 32)
  • Exomes 𝑓: 0.022 (4160 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 5.06

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=0.0017544031).
• BP6: Variant 2-26527901-G-A is Benign according to our data. Variant chr2-26527901-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 21824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26527901-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.158C>T	p.Ala53Val	missense_variant	3/47	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2	c.158C>T	p.Ala53Val	missense_variant	3/46		NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.158C>T	p.Ala53Val	missense_variant	3/47	1	NM_194248.3	ENSP00000272371	A1
OTOF	ENST00000403946.7	c.158C>T	p.Ala53Val	missense_variant	3/46	5		ENSP00000385255	P4

Frequencies

GnomAD3 genomes AF: 0.0321 AC: 4884 AN: 152066 Hom.: 524 Cov.: 32

Gnomad AFR AF: 0.00514

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.0177

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00279

Gnomad OTH AF: 0.0397

GnomAD3 exomes AF: 0.0655 AC: 16470 AN: 251374 Hom.: 2310 AF XY: 0.0548 AC XY: 7448 AN XY: 135894

Gnomad AFR exome AF: 0.00462

Gnomad AMR exome AF: 0.283

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.278

Gnomad SAS exome AF: 0.0197

Gnomad FIN exome AF: 0.0136

Gnomad NFE exome AF: 0.00289

Gnomad OTH exome AF: 0.0404

GnomAD4 exome AF: 0.0218 AC: 31808 AN: 1461638 Hom.: 4160 Cov.: 32 AF XY: 0.0206 AC XY: 14987 AN XY: 727134

Gnomad4 AFR exome AF: 0.00296

Gnomad4 AMR exome AF: 0.268

Gnomad4 ASJ exome AF: 0.00130

Gnomad4 EAS exome AF: 0.322

Gnomad4 SAS exome AF: 0.0204

Gnomad4 FIN exome AF: 0.0150

Gnomad4 NFE exome AF: 0.00240

Gnomad4 OTH exome AF: 0.0280

GnomAD4 genome AF: 0.0322 AC: 4894 AN: 152184 Hom.: 529 Cov.: 32 AF XY: 0.0372 AC XY: 2771 AN XY: 74396

Gnomad4 AFR AF: 0.00513

Gnomad4 AMR AF: 0.171

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.291

Gnomad4 SAS AF: 0.0234

Gnomad4 FIN AF: 0.0177

Gnomad4 NFE AF: 0.00279

Gnomad4 OTH AF: 0.0388

Alfa AF: 0.0140 Hom.: 400

Bravo AF: 0.0460

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.0537 AC: 6520

Asia WGS AF: 0.121 AC: 420 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 23, 2010	Ala53Val in exon 3 of OTOF: This variant is not expected to have clinical signif icance because it was detected in normal hearing controls and it involves a chan ge at a position that is not conserved (Jiminez 2007, Varga 2006). In addition, it has been seen in an unpublished study with a minor allele frequency of 3% and has been identified in 10/122 (8%) of individuals tested by our laboratory. Thi s variant is also listed in dbSNP (rs1879761 - no frequency data available). -

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Autosomal recessive nonsyndromic hearing loss 9 Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 04, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	0.094
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	0.011	P;P
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.11
Sift	Benign	0.15	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.18	B;.
Vest4		0.47
MPC		0.22
ClinPred		0.0084	T
GERP RS		4.5
Varity_R		0.18
gMVP		0.48

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: rs1879761; hg19: chr2-26750769; COSMIC: COSV55503668;