rs41288779

Variant names:

• chr2-26489693-C-T
• rs41288779
• NM_194248.3:c.945G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_194248.3(OTOF):​c.945G>A​(p.Lys315Lys) 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:6 O:1
• Conservation: PhyloP100: -0.0250
• Publications: 8 publications found

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]

OTOF Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 21864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.945G>A	p.Lys315Lys	synonymous_variant	Exon 10 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2	c.945G>A	p.Lys315Lys	synonymous_variant	Exon 10 of 46		NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.945G>A	p.Lys315Lys	synonymous_variant	Exon 10 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000403946.7	c.945G>A	p.Lys315Lys	synonymous_variant	Exon 10 of 46	5		ENSP00000385255.3

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

GnomAD2 exomes AF: 0.0539 AC: 13512 AN: 250800 AF XY: 0.0525

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 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

African (AFR) AF: 0.116 AC: 3868 AN: 33462

American (AMR) AF: 0.0434 AC: 1943 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0556 AC: 1453 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0397 AC: 3428 AN: 86244

European-Finnish (FIN) AF: 0.0395 AC: 2071 AN: 52370

Middle Eastern (MID) AF: 0.0224 AC: 129 AN: 5768

European-Non Finnish (NFE) AF: 0.0709 AC: 78785 AN: 1111328

Other (OTH) AF: 0.0573 AC: 3457 AN: 60366

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

African (AFR) AF: 0.114 AC: 4732 AN: 41558

American (AMR) AF: 0.0433 AC: 663 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0562 AC: 195 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.0350 AC: 169 AN: 4830

European-Finnish (FIN) AF: 0.0357 AC: 380 AN: 10630

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0664 AC: 4515 AN: 68018

Other (OTH) AF: 0.0460 AC: 97 AN: 2110

Alfa AF: 0.0758 Hom.: 446

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:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

May 09, 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. -

Mar 02, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	9.9
DANN	Benign	0.59
PhyloP100		-0.025
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41288779; hg19: chr2-26712561; COSMIC: COSV108092256;