rs72853741

chr2-26479640-G-A

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.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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.0160

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=-0.48).
• 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 58 AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0258 AC: 3929 AN: 152234 Hom.: 58 Cov.: 34

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.: 62 AF XY: 0.0181 AC XY: 2456 AN XY: 135510

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.: 34 AF XY: 0.0210 AC XY: 15270 AN XY: 726228

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.: 58 Cov.: 34 AF XY: 0.0245 AC XY: 1828 AN XY: 74490

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.: 29

Bravo AF: 0.0273

Asia WGS AF: 0.00635 AC: 23 AN: 3478

EpiCase AF: 0.0244

EpiControl AF: 0.0244

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -

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

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. -
not provided, no classification provided	literature only	GeneReviews	-	- -

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

Other links and lift over

dbSNP: rs72853741; hg19: chr2-26702508; COSMIC: COSV55516132; COSMIC: COSV55516132;