NM_194248.3:c.4629-9C>T

Variant names:

• chr2-26465851-G-A
• rs72853726
• NM_194248.3:c.4629-9C>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.4629-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00331 in 1,614,234 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (26 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (42 hom.)
• Consequence: OTOF NM_194248.3 intron
• Scores: Splicing: ADA: 0.00001618
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.33

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 2-26465851-G-A is Benign according to our data. Variant chr2-26465851-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 48239.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 = 0.0117 (1790/152360) while in subpopulation AFR AF= 0.0373 (1552/41578). AF 95% confidence interval is 0.0358. There are 26 homozygotes in gnomad4. There are 855 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.4629-9C>T		intron_variant	Intron 37 of 46	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.2328-9C>T		intron_variant	Intron 20 of 28	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.4629-9C>T		intron_variant	Intron 37 of 46	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.2328-9C>T		intron_variant	Intron 20 of 28	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1776 AN: 152242 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.0371

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.00456 AC: 1146 AN: 251350 Hom.: 19 AF XY: 0.00394 AC XY: 536 AN XY: 135878

Gnomad AFR exome AF: 0.0394

Gnomad AMR exome AF: 0.00567

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00258

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00171

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00243 AC: 3551 AN: 1461874 Hom.: 42 Cov.: 32 AF XY: 0.00237 AC XY: 1721 AN XY: 727232

Gnomad4 AFR exome AF: 0.0412

Gnomad4 AMR exome AF: 0.00590

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00274

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.00530

GnomAD4 genome AF: 0.0117 AC: 1790 AN: 152360 Hom.: 26 Cov.: 33 AF XY: 0.0115 AC XY: 855 AN XY: 74494

Gnomad4 AFR AF: 0.0373

Gnomad4 AMR AF: 0.00719

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00131

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00682 Hom.: 13

Bravo AF: 0.0137

Asia WGS AF: 0.00751 AC: 27 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 30, 2018

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

4629-9C>T in exon 38 of OTOF: This variant is not expected to have clinical sign ificance because it has been identified in 3.9% (147/3738) of chromosomes from a broad African American population and 0.15% (11/7020) of chromosomes from a bro ad European American population (dbSNP rs72853726). -

Autosomal recessive nonsyndromic hearing loss 9 Benign:1

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	-0.84
CADD	Benign	0.24
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0
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: rs72853726; hg19: chr2-26688719;