rs13004993

Variant names:

• chr2-26479544-G-A
• rs13004993
• NM_194248.3:c.2022C>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.2022C>T​(p.Asp674Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0338 in 1,611,682 control chromosomes in the GnomAD database, including 1,243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (122 hom., cov: 34)
  • Exomes 𝑓: 0.034 (1121 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -2.64

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=-0.97).
• BP6: Variant 2-26479544-G-A is Benign according to our data. Variant chr2-26479544-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 21829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26479544-G-A is described in Lovd as [Benign]. Variant chr2-26479544-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.64 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0288 (4381/152284) while in subpopulation NFE AF= 0.0362 (2464/68010). AF 95% confidence interval is 0.035. There are 122 homozygotes in gnomad4. There are 2333 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 122 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.2022C>T	p.Asp674Asp	synonymous_variant	Exon 17 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2	c.2022C>T	p.Asp674Asp	synonymous_variant	Exon 17 of 46		NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.2022C>T	p.Asp674Asp	synonymous_variant	Exon 17 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000403946.7	c.2022C>T	p.Asp674Asp	synonymous_variant	Exon 17 of 46	5		ENSP00000385255.3

Frequencies

GnomAD3 genomes AF: 0.0288 AC: 4380 AN: 152166 Hom.: 122 Cov.: 34

Gnomad AFR AF: 0.00724

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.0216

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0362

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.0283 AC: 6957 AN: 245784 Hom.: 178 AF XY: 0.0283 AC XY: 3776 AN XY: 133616

Gnomad AFR exome AF: 0.00576

Gnomad AMR exome AF: 0.0139

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00423

Gnomad FIN exome AF: 0.0988

Gnomad NFE exome AF: 0.0349

Gnomad OTH exome AF: 0.0313

GnomAD4 exome AF: 0.0344 AC: 50132 AN: 1459398 Hom.: 1121 Cov.: 35 AF XY: 0.0337 AC XY: 24450 AN XY: 725882

Gnomad4 AFR exome AF: 0.00571

Gnomad4 AMR exome AF: 0.0146

Gnomad4 ASJ exome AF: 0.0131

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00394

Gnomad4 FIN exome AF: 0.0926

Gnomad4 NFE exome AF: 0.0377

Gnomad4 OTH exome AF: 0.0305

GnomAD4 genome AF: 0.0288 AC: 4381 AN: 152284 Hom.: 122 Cov.: 34 AF XY: 0.0313 AC XY: 2333 AN XY: 74458

Gnomad4 AFR AF: 0.00724

Gnomad4 AMR AF: 0.0216

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.108

Gnomad4 NFE AF: 0.0362

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.0322 Hom.: 133

Bravo AF: 0.0222

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Dec 28, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

not specified Benign:2

Feb 19, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 16, 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. -

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

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. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.035
DANN	Benign	0.57

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: rs13004993; hg19: chr2-26702412;