rs368329882

Variant names:

• chr2-26472662-A-G
• rs368329882
• NM_194248.3:c.3734-13T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-26472662-A-G
• chr2-26472662-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_194248.3(OTOF):​c.3734-13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,612,380 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (2 hom., cov: 33)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: OTOF NM_194248.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.58

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-26472662-A-G is Benign according to our data. Variant chr2-26472662-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 48224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00104 (158/152342) while in subpopulation AFR AF= 0.00361 (150/41584). AF 95% confidence interval is 0.00314. There are 2 homozygotes in gnomad4. There are 69 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.3734-13T>C		intron_variant	Intron 29 of 46	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.1493-73T>C		intron_variant	Intron 12 of 28	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.3734-13T>C		intron_variant	Intron 29 of 46	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.1493-73T>C		intron_variant	Intron 12 of 28	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 157 AN: 152224 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00359

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000202 AC: 50 AN: 247922 Hom.: 2 AF XY: 0.0000966 AC XY: 13 AN XY: 134534

Gnomad AFR exome AF: 0.00296

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000895

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.0000788 AC: 115 AN: 1460038 Hom.: 0 Cov.: 32 AF XY: 0.0000702 AC XY: 51 AN XY: 726248

Gnomad4 AFR exome AF: 0.00296

Gnomad4 AMR exome AF: 0.0000673

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.00104 AC: 158 AN: 152342 Hom.: 2 Cov.: 33 AF XY: 0.000926 AC XY: 69 AN XY: 74502

Gnomad4 AFR AF: 0.00361

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 27, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

3734-13T>C in intron 29 of OTOF: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not predicted to impact the splice consensus sequence and has been identified in 0.1% (5/3734) o f African American chromosomes from a broad population by the NHLBI Exome sequen cing project (http://evs.gs.washington.edu/EVS/). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.9
DANN	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs368329882; hg19: chr2-26695530;