rs2272071

chr2-26465794-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.4677G>A(p.Val1559=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 1,614,194 control chromosomes in the GnomAD database, including 1,023 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (180 hom., cov: 33)
  • Exomes 𝑓: 0.022 (843 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.230

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=-0.37).
• BP6: Variant 2-26465794-C-T is Benign according to our data. Variant chr2-26465794-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 21853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26465794-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.4677G>A	p.Val1559=	synonymous_variant	38/47	ENST00000272371.7
OTOF	NM_194323.3	c.2376G>A	p.Val792=	synonymous_variant	21/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.4677G>A	p.Val1559=	synonymous_variant	38/47	1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.2376G>A	p.Val792=	synonymous_variant	21/29	1	NM_194323.3

Frequencies

GnomAD3 genomes AF: 0.0396 AC: 6025 AN: 152182 Hom.: 179 Cov.: 33

Gnomad AFR AF: 0.0694

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.0389

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.0509

Gnomad FIN AF: 0.0420

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0347 AC: 8737 AN: 251444 Hom.: 298 AF XY: 0.0337 AC XY: 4582 AN XY: 135910

Gnomad AFR exome AF: 0.0686

Gnomad AMR exome AF: 0.0364

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.134

Gnomad SAS exome AF: 0.0449

Gnomad FIN exome AF: 0.0383

Gnomad NFE exome AF: 0.0134

Gnomad OTH exome AF: 0.0266

GnomAD4 exome AF: 0.0218 AC: 31847 AN: 1461894 Hom.: 843 Cov.: 32 AF XY: 0.0223 AC XY: 16188 AN XY: 727248

Gnomad4 AFR exome AF: 0.0706

Gnomad4 AMR exome AF: 0.0380

Gnomad4 ASJ exome AF: 0.00176

Gnomad4 EAS exome AF: 0.140

Gnomad4 SAS exome AF: 0.0447

Gnomad4 FIN exome AF: 0.0346

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.0298

GnomAD4 genome AF: 0.0396 AC: 6034 AN: 152300 Hom.: 180 Cov.: 33 AF XY: 0.0411 AC XY: 3060 AN XY: 74470

Gnomad4 AFR AF: 0.0695

Gnomad4 AMR AF: 0.0388

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.138

Gnomad4 SAS AF: 0.0503

Gnomad4 FIN AF: 0.0420

Gnomad4 NFE AF: 0.0138

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0182 Hom.: 82

Bravo AF: 0.0408

Asia WGS AF: 0.0980 AC: 341 AN: 3478

EpiCase AF: 0.0134

EpiControl AF: 0.0132

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 19, 2008	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 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

Likely 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 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, no classification provided	literature only	GeneReviews	-	- -

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	-0.37
Cadd	Benign	3.7
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2272071; hg19: chr2-26688662; COSMIC: COSV55498931;