rs116990436

chr2-26461811-G-Achr2-26461811-G-Cchr2-26461811-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_194248.3(OTOF):c.5418C>T(p.Ile1806=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,614,176 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (39 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.22

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=-0.48).
• BP6: Variant 2-26461811-G-A is Benign according to our data. Variant chr2-26461811-G-A is described in ClinVar as [Benign]. Clinvar id is 48261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.22 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00175 (267/152290) while in subpopulation EAS AF= 0.0421 (218/5184). AF 95% confidence interval is 0.0375. There are 7 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.5418C>T	p.Ile1806=	synonymous_variant	43/47	ENST00000272371.7
OTOF	NM_194323.3	c.3117C>T	p.Ile1039=	synonymous_variant	26/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.5418C>T	p.Ile1806=	synonymous_variant	43/47	1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.3117C>T	p.Ile1039=	synonymous_variant	26/29	1	NM_194323.3

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 152172 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0420

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00361 AC: 909 AN: 251482 Hom.: 27 AF XY: 0.00350 AC XY: 476 AN XY: 135914

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0475

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00126 AC: 1840 AN: 1461886 Hom.: 39 Cov.: 33 AF XY: 0.00123 AC XY: 891 AN XY: 727244

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0397

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00321

GnomAD4 genome AF: 0.00175 AC: 267 AN: 152290 Hom.: 7 Cov.: 32 AF XY: 0.00167 AC XY: 124 AN XY: 74456

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0421

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.000231 Hom.: 1

Bravo AF: 0.00180

Asia WGS AF: 0.0150 AC: 53 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 01, 2011	Ile1806Ile in exon 43 of OTOF: This variant is not expected to have clinical sig nificance because it has been identified in a similar frequency in Chinese cases (5/146 (3.4%) chromosomes) and controls (8/192 (4.2%) chromosomes) (Wang 2010). In addition, this variant has been identified by our laboratory in three indivi duals; two of whom have another genetic etiology for their hearing loss. Further more, this variant does not alter an amino acid residue and is not located near a splice junction. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Autosomal recessive nonsyndromic hearing loss 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	2.8
Dann	Benign	0.75

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: rs116990436; hg19: chr2-26684679; COSMIC: COSV55495166; COSMIC: COSV55495166;