rs2272071

Variant names:

• chr2-26465794-C-T
• rs2272071
• NM_194248.3:c.4677G>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.4677G>A​(p.Val1559Val) 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:5 O:1
• Conservation: PhyloP100: 0.230
• Publications: 11 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=-0.37).
• BP6: Variant 2-26465794-C-T is Benign according to our data. Variant chr2-26465794-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.4677G>A	p.Val1559Val	synonymous_variant	Exon 38 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.2376G>A	p.Val792Val	synonymous_variant	Exon 21 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.4677G>A	p.Val1559Val	synonymous_variant	Exon 38 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.2376G>A	p.Val792Val	synonymous_variant	Exon 21 of 29	1	NM_194323.3	ENSP00000344521.3

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

GnomAD2 exomes AF: 0.0347 AC: 8737 AN: 251444 AF XY: 0.0337

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 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

African (AFR) AF: 0.0706 AC: 2364 AN: 33480

American (AMR) AF: 0.0380 AC: 1700 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 46 AN: 26136

East Asian (EAS) AF: 0.140 AC: 5551 AN: 39700

South Asian (SAS) AF: 0.0447 AC: 3857 AN: 86258

European-Finnish (FIN) AF: 0.0346 AC: 1847 AN: 53420

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5768

European-Non Finnish (NFE) AF: 0.0131 AC: 14585 AN: 1112012

Other (OTH) AF: 0.0298 AC: 1799 AN: 60396

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

African (AFR) AF: 0.0695 AC: 2888 AN: 41552

American (AMR) AF: 0.0388 AC: 594 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.138 AC: 714 AN: 5160

South Asian (SAS) AF: 0.0503 AC: 243 AN: 4832

European-Finnish (FIN) AF: 0.0420 AC: 446 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0138 AC: 938 AN: 68040

Other (OTH) AF: 0.0336 AC: 71 AN: 2114

Alfa AF: 0.0198 Hom.: 123

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:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Aug 03, 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. -

Feb 19, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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 12, 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	-0.37
CADD	Benign	3.7
DANN	Benign	0.74
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2272071; hg19: chr2-26688662; COSMIC: COSV55498931;