rs45442103

Variant names:

• chr2-26460909-G-A
• rs45442103
• NM_194248.3:c.5655C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-26460909-G-A
• chr2-26460909-G-T

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.5655C>T​(p.Arg1885Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0552 in 1,614,042 control chromosomes in the GnomAD database, including 2,762 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (202 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2560 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.0630
• Publications: 10 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=-0.44).
• BP6: Variant 2-26460909-G-A is Benign according to our data. Variant chr2-26460909-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.063 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.5655C>T	p.Arg1885Arg	synonymous_variant	Exon 44 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.3354C>T	p.Arg1118Arg	synonymous_variant	Exon 27 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.5655C>T	p.Arg1885Arg	synonymous_variant	Exon 44 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.3354C>T	p.Arg1118Arg	synonymous_variant	Exon 27 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.0456 AC: 6942 AN: 152160 Hom.: 202 Cov.: 32

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.0582

Gnomad ASJ AF: 0.0781

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0242

Gnomad FIN AF: 0.0648

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0624

Gnomad OTH AF: 0.0651

GnomAD2 exomes AF: 0.0458 AC: 11508 AN: 251370 AF XY: 0.0468

Gnomad AFR exome AF: 0.00880

Gnomad AMR exome AF: 0.0292

Gnomad ASJ exome AF: 0.0821

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0645

Gnomad NFE exome AF: 0.0618

Gnomad OTH exome AF: 0.0548

GnomAD4 exome AF: 0.0562 AC: 82102 AN: 1461764 Hom.: 2560 Cov.: 36 AF XY: 0.0556 AC XY: 40449 AN XY: 727196

African (AFR) AF: 0.00917 AC: 307 AN: 33480

American (AMR) AF: 0.0314 AC: 1402 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0807 AC: 2110 AN: 26134

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0251 AC: 2165 AN: 86258

European-Finnish (FIN) AF: 0.0625 AC: 3340 AN: 53398

Middle Eastern (MID) AF: 0.0570 AC: 329 AN: 5768

European-Non Finnish (NFE) AF: 0.0622 AC: 69153 AN: 1111912

Other (OTH) AF: 0.0545 AC: 3292 AN: 60394

GnomAD4 genome AF: 0.0456 AC: 6939 AN: 152278 Hom.: 202 Cov.: 32 AF XY: 0.0448 AC XY: 3339 AN XY: 74458

African (AFR) AF: 0.0117 AC: 486 AN: 41554

American (AMR) AF: 0.0581 AC: 889 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0781 AC: 271 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.0238 AC: 115 AN: 4822

European-Finnish (FIN) AF: 0.0648 AC: 688 AN: 10620

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0625 AC: 4248 AN: 68018

Other (OTH) AF: 0.0644 AC: 136 AN: 2112

Alfa AF: 0.0554 Hom.: 189

Bravo AF: 0.0443

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.0642

EpiControl AF: 0.0624

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7 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 15, 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:3

Jan 29, 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

- -

Aug 10, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.44
CADD	Benign	6.4
DANN	Benign	0.87
PhyloP100		0.063
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs45442103; hg19: chr2-26683777; COSMIC: COSV55503150; COSMIC: COSV55503150;