rs149236286

Variant names:

• chr2-26467129-G-A
• rs149236286
• NM_194248.3:c.4332C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-26467129-G-A
• chr2-26467129-G-C
• chr2-26467129-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_194248.3(OTOF):​c.4332C>T​(p.Thr1444Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,613,904 control chromosomes in the GnomAD database, including 371 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (18 hom., cov: 32)
  • Exomes 𝑓: 0.019 (353 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -4.61

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 2-26467129-G-A is Benign according to our data. Variant chr2-26467129-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48233.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-4.61 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0146 (2221/152206) while in subpopulation NFE AF= 0.0195 (1329/68010). AF 95% confidence interval is 0.0187. There are 18 homozygotes in gnomad4. There are 1014 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.4332C>T	p.Thr1444Thr	synonymous_variant	Exon 35 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.2031C>T	p.Thr677Thr	synonymous_variant	Exon 18 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.4332C>T	p.Thr1444Thr	synonymous_variant	Exon 35 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.2031C>T	p.Thr677Thr	synonymous_variant	Exon 18 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2219 AN: 152088 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00886

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.0199

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.0144 AC: 3622 AN: 251204 Hom.: 29 AF XY: 0.0146 AC XY: 1988 AN XY: 135808

Gnomad AFR exome AF: 0.00911

Gnomad AMR exome AF: 0.00740

Gnomad ASJ exome AF: 0.0190

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00300

Gnomad FIN exome AF: 0.0221

Gnomad NFE exome AF: 0.0208

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.0195 AC: 28459 AN: 1461698 Hom.: 353 Cov.: 35 AF XY: 0.0189 AC XY: 13757 AN XY: 727170

Gnomad4 AFR exome AF: 0.00830

Gnomad4 AMR exome AF: 0.00794

Gnomad4 ASJ exome AF: 0.0179

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00322

Gnomad4 FIN exome AF: 0.0227

Gnomad4 NFE exome AF: 0.0223

Gnomad4 OTH exome AF: 0.0168

GnomAD4 genome AF: 0.0146 AC: 2221 AN: 152206 Hom.: 18 Cov.: 32 AF XY: 0.0136 AC XY: 1014 AN XY: 74398

Gnomad4 AFR AF: 0.00891

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.0199

Gnomad4 NFE AF: 0.0195

Gnomad4 OTH AF: 0.0119

Alfa AF: 0.0137 Hom.: 8

Bravo AF: 0.0141

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0220

EpiControl AF: 0.0212

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Oct 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Jul 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19461658, 18381613) -

Aug 31, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 9 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Oct 18, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Thr1444Thr in exon 35 of OTOF: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located near a splice junction, is reported as benign in one publication (Rodriguez-Ballestero s 2008) and has been identified in 5/211 (2.4%) probands tested by our laborator y (at least 2 have Usher syndrome). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.0030
DANN	Benign	0.69

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: rs149236286; hg19: chr2-26689997; COSMIC: COSV55515962; COSMIC: COSV55515962;