2-26516555-T-C

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.372A>G(p.Thr124=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 1,611,062 control chromosomes in the GnomAD database, including 70,420 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5628 hom., cov: 32)
  • Exomes 𝑓: 0.29 (64792 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -9.09

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=-1.03).
• BP6: Variant 2-26516555-T-C is Benign according to our data. Variant chr2-26516555-T-C is described in ClinVar as [Benign]. Clinvar id is 21847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26516555-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-9.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.372A>G	p.Thr124=	synonymous_variant	5/47	ENST00000272371.7
OTOF	NM_001287489.2	c.372A>G	p.Thr124=	synonymous_variant	5/46

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.372A>G	p.Thr124=	synonymous_variant	5/47	1	NM_194248.3	A1
OTOF	ENST00000403946.7	c.372A>G	p.Thr124=	synonymous_variant	5/46	5		P4

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36615 AN: 151986 Hom.: 5627 Cov.: 32

Gnomad AFR AF: 0.0695

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.216

GnomAD3 exomes AF: 0.301 AC: 75120 AN: 249402 Hom.: 12669 AF XY: 0.299 AC XY: 40327 AN XY: 135046

Gnomad AFR exome AF: 0.0629

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.203

Gnomad EAS exome AF: 0.549

Gnomad SAS exome AF: 0.245

Gnomad FIN exome AF: 0.404

Gnomad NFE exome AF: 0.298

Gnomad OTH exome AF: 0.279

GnomAD4 exome AF: 0.292 AC: 425708 AN: 1458958 Hom.: 64792 Cov.: 43 AF XY: 0.291 AC XY: 211009 AN XY: 725960

Gnomad4 AFR exome AF: 0.0580

Gnomad4 AMR exome AF: 0.309

Gnomad4 ASJ exome AF: 0.203

Gnomad4 EAS exome AF: 0.467

Gnomad4 SAS exome AF: 0.248

Gnomad4 FIN exome AF: 0.401

Gnomad4 NFE exome AF: 0.293

Gnomad4 OTH exome AF: 0.283

GnomAD4 genome AF: 0.241 AC: 36638 AN: 152104 Hom.: 5628 Cov.: 32 AF XY: 0.247 AC XY: 18357 AN XY: 74346

Gnomad4 AFR AF: 0.0696

Gnomad4 AMR AF: 0.250

Gnomad4 ASJ AF: 0.201

Gnomad4 EAS AF: 0.518

Gnomad4 SAS AF: 0.263

Gnomad4 FIN AF: 0.412

Gnomad4 NFE AF: 0.295

Gnomad4 OTH AF: 0.223

Alfa AF: 0.271 Hom.: 1855

Bravo AF: 0.224

Asia WGS AF: 0.432 AC: 1502 AN: 3478

EpiCase AF: 0.282

EpiControl AF: 0.277

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 02, 2007	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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. -

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

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.013
Dann	Benign	0.26

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: rs11687696; hg19: chr2-26739423; COSMIC: COSV55510690;