rs41288779

chr2-26489693-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_194248.3(OTOF):c.945G>A(p.Lys315=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0657 in 1,612,408 control chromosomes in the GnomAD database, including 3,853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (481 hom., cov: 33)
  • Exomes 𝑓: 0.065 (3372 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -0.0250

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 2-26489693-C-T is Benign according to our data. Variant chr2-26489693-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 21864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26489693-C-T is described in Lovd as [Benign]. Variant chr2-26489693-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.025 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.945G>A	p.Lys315=	synonymous_variant	10/47	ENST00000272371.7
OTOF	NM_001287489.2	c.945G>A	p.Lys315=	synonymous_variant	10/46

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.945G>A	p.Lys315=	synonymous_variant	10/47	1	NM_194248.3	A1
OTOF	ENST00000403946.7	c.945G>A	p.Lys315=	synonymous_variant	10/46	5		P4

Frequencies

GnomAD3 genomes AF: 0.0713 AC: 10849 AN: 152202 Hom.: 481 Cov.: 33

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.0434

Gnomad ASJ AF: 0.0562

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0348

Gnomad FIN AF: 0.0357

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0664

Gnomad OTH AF: 0.0465

GnomAD3 exomes AF: 0.0539 AC: 13512 AN: 250800 Hom.: 467 AF XY: 0.0525 AC XY: 7134 AN XY: 135820

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.0433

Gnomad ASJ exome AF: 0.0546

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0379

Gnomad FIN exome AF: 0.0376

Gnomad NFE exome AF: 0.0649

Gnomad OTH exome AF: 0.0463

GnomAD4 exome AF: 0.0652 AC: 95135 AN: 1460088 Hom.: 3372 Cov.: 31 AF XY: 0.0641 AC XY: 46557 AN XY: 726374

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.0434

Gnomad4 ASJ exome AF: 0.0556

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0397

Gnomad4 FIN exome AF: 0.0395

Gnomad4 NFE exome AF: 0.0709

Gnomad4 OTH exome AF: 0.0573

GnomAD4 genome AF: 0.0713 AC: 10853 AN: 152320 Hom.: 481 Cov.: 33 AF XY: 0.0681 AC XY: 5073 AN XY: 74478

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.0433

Gnomad4 ASJ AF: 0.0562

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0350

Gnomad4 FIN AF: 0.0357

Gnomad4 NFE AF: 0.0664

Gnomad4 OTH AF: 0.0460

Alfa AF: 0.0699 Hom.: 211

Bravo AF: 0.0737

Asia WGS AF: 0.0260 AC: 90 AN: 3478

EpiCase AF: 0.0586

EpiControl AF: 0.0600

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	PreventionGenetics, part of Exact Sciences	-	- -
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:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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	-0.32
Cadd	Benign	9.9
Dann	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs41288779; hg19: chr2-26712561;