rs61746988

chr2-26479541-C-T

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.2025G>A(p.Glu675=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00865 in 1,611,448 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0087 (79 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.461

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=-0.68).
• BP6: Variant 2-26479541-C-T is Benign according to our data. Variant chr2-26479541-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 21830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26479541-C-T is described in Lovd as [Likely_benign]. Variant chr2-26479541-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.461 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00874 (12759/1459150) while in subpopulation MID AF= 0.017 (98/5764). AF 95% confidence interval is 0.0143. There are 79 homozygotes in gnomad4_exome. There are 6394 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.2025G>A	p.Glu675=	synonymous_variant	17/47	ENST00000272371.7
OTOF	NM_001287489.2	c.2025G>A	p.Glu675=	synonymous_variant	17/46

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.2025G>A	p.Glu675=	synonymous_variant	17/47	1	NM_194248.3	A1
OTOF	ENST00000403946.7	c.2025G>A	p.Glu675=	synonymous_variant	17/46	5		P4

Frequencies

GnomAD3 genomes AF: 0.00780 AC: 1187 AN: 152180 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00913

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00793 AC: 1942 AN: 244822 Hom.: 13 AF XY: 0.00781 AC XY: 1039 AN XY: 133104

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00612

Gnomad ASJ exome AF: 0.0202

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00232

Gnomad FIN exome AF: 0.0100

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.00874 AC: 12759 AN: 1459150 Hom.: 79 Cov.: 34 AF XY: 0.00881 AC XY: 6394 AN XY: 725712

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00591

Gnomad4 ASJ exome AF: 0.0197

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00214

Gnomad4 FIN exome AF: 0.0101

Gnomad4 NFE exome AF: 0.00949

Gnomad4 OTH exome AF: 0.00965

GnomAD4 genome AF: 0.00778 AC: 1185 AN: 152298 Hom.: 9 Cov.: 33 AF XY: 0.00826 AC XY: 615 AN XY: 74456

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.0122

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00913

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0102 Hom.: 3

Bravo AF: 0.00667

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2019	This variant is associated with the following publications: (PMID: 16371502) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	OTOF: BP4, BP7, BS1, BS2 -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 11, 2010	- -

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

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	1.8
Dann	Benign	0.33

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: rs61746988; hg19: chr2-26702409;