rs72853741

Positions:

chr2-26479640-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_194248.3(OTOF):c.1926C>T(p.Asn642=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0221 in 1,612,446 control chromosomes in the GnomAD database, including 489 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 58 hom., cov: 34)

Exomes 𝑓: 0.022 ( 431 hom. )

Consequence

OTOF
NM_194248.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 0.0160

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 2-26479640-G-A is Benign according to our data. Variant chr2-26479640-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 21828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.016 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0258 (3931/152352) while in subpopulation AFR AF= 0.0445 (1850/41586). AF 95% confidence interval is 0.0428. There are 58 homozygotes in gnomad4. There are 1828 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 58 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.1926C>T	p.Asn642=	synonymous_variant	17/47	ENST00000272371.7
OTOF	NM_001287489.2 linkuse as main transcript	c.1926C>T	p.Asn642=	synonymous_variant	17/46

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.1926C>T	p.Asn642=	synonymous_variant	17/47	1	NM_194248.3	A1	Q9HC10-1
OTOF	ENST00000403946.7 linkuse as main transcript	c.1926C>T	p.Asn642=	synonymous_variant	17/46	5		P4	Q9HC10-5

Frequencies

GnomAD3 genomes

AF:

0.0258

AC:

3929

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0445

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0194

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0200

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0208

Gnomad OTH

AF:

0.0215

GnomAD3 exomes

AF:

0.0186

AC:

4637

AN:

249340

Hom.:

AF XY:

0.0181

AC XY:

2456

AN XY:

135510

show subpopulations

Gnomad AFR exome

AF:

0.0460

Gnomad AMR exome

AF:

0.0131

Gnomad ASJ exome

AF:

0.0221

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00337

Gnomad FIN exome

AF:

0.0221

Gnomad NFE exome

AF:

0.0225

Gnomad OTH exome

AF:

0.0205

GnomAD4 exome

AF:

0.0217

AC:

31691

AN:

1460094

Hom.:

431

Cov.:

AF XY:

0.0210

AC XY:

15270

AN XY:

726228

show subpopulations

Gnomad4 AFR exome

AF:

0.0471

Gnomad4 AMR exome

AF:

0.0138

Gnomad4 ASJ exome

AF:

0.0210

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00356

Gnomad4 FIN exome

AF:

0.0229

Gnomad4 NFE exome

AF:

0.0234

Gnomad4 OTH exome

AF:

0.0216

GnomAD4 genome

AF:

0.0258

AC:

3931

AN:

152352

Hom.:

Cov.:

AF XY:

0.0245

AC XY:

1828

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0445

Gnomad4 AMR

AF:

0.0193

Gnomad4 ASJ

AF:

0.0236

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.0200

Gnomad4 NFE

AF:

0.0208

Gnomad4 OTH

AF:

0.0213

Alfa

AF:

0.0235

Hom.:

Bravo

AF:

0.0273

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.0244

EpiControl

AF:

0.0244

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 02, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 06, 2010	Asn642Asn in exon 17 of OTOF: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located near a splice junction, is listed in dbSNP (rs72853741 ? no frequency data), has been f ound in 5/150 (3%) cases in our laboratory (two of whom have other hearing loss etiologies), and is reported as benign in two publications (Smith 2008, Varga 20 06). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive nonsyndromic hearing loss 9

Benign:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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

-0.48

CADD

Benign

1.3

DANN

Benign

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over