rs116525289

Variant names:

• chr2-26537725-G-A
• rs116525289
• NM_194248.3:c.129C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_194248.3(OTOF):​c.129C>T​(p.Asp43Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0076 in 1,554,472 control chromosomes in the GnomAD database, including 524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (71 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (453 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.56

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 2-26537725-G-A is Benign according to our data. Variant chr2-26537725-G-A is described in ClinVar as [Benign]. Clinvar id is 48167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.56 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.129C>T	p.Asp43Asp	synonymous_variant	Exon 2 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2	c.129C>T	p.Asp43Asp	synonymous_variant	Exon 2 of 46		NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.129C>T	p.Asp43Asp	synonymous_variant	Exon 2 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000403946.7	c.129C>T	p.Asp43Asp	synonymous_variant	Exon 2 of 46	5		ENSP00000385255.3

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2659 AN: 152146 Hom.: 72 Cov.: 33

Gnomad AFR AF: 0.0420

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00831

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.0137 AC: 2224 AN: 162332 Hom.: 94 AF XY: 0.0130 AC XY: 1112 AN XY: 85662

Gnomad AFR exome AF: 0.0404

Gnomad AMR exome AF: 0.00423

Gnomad ASJ exome AF: 0.000347

Gnomad EAS exome AF: 0.111

Gnomad SAS exome AF: 0.0119

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.00994

GnomAD4 exome AF: 0.00653 AC: 9156 AN: 1402208 Hom.: 453 Cov.: 30 AF XY: 0.00655 AC XY: 4536 AN XY: 692044

Gnomad4 AFR exome AF: 0.0402

Gnomad4 AMR exome AF: 0.00486

Gnomad4 ASJ exome AF: 0.000277

Gnomad4 EAS exome AF: 0.143

Gnomad4 SAS exome AF: 0.0107

Gnomad4 FIN exome AF: 0.00107

Gnomad4 NFE exome AF: 0.000852

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.0174 AC: 2652 AN: 152264 Hom.: 71 Cov.: 33 AF XY: 0.0178 AC XY: 1327 AN XY: 74448

Gnomad4 AFR AF: 0.0418

Gnomad4 AMR AF: 0.00843

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.00973

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00630 Hom.: 10

Bravo AF: 0.0193

Asia WGS AF: 0.0440 AC: 151 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Oct 25, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 03, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 27, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Asp43Asp in exon 2 of OTOF: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue, is not located within th e splice consensus sequence, has been identified in 3.2% (118/3708) of African A merican chromosomes from a broad population by the NHLBI Exome sequencing projec t (http://evs.gs.washington.edu/EVS/; dbSNP rs116525289). -

not provided Benign:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal recessive nonsyndromic hearing loss 9 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Benign	0.70

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: rs116525289; hg19: chr2-26760593; COSMIC: COSV55523655;