rs73920286

chr2-26477633-G-Achr2-26477633-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_194248.3(OTOF):c.2315+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00682 in 1,611,668 control chromosomes in the GnomAD database, including 530 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (275 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (255 hom.)
• Consequence: OTOF NM_194248.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.59

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=-0.85).
• BP6: Variant 2-26477633-G-A is Benign according to our data. Variant chr2-26477633-G-A is described in ClinVar as [Benign]. Clinvar id is 263081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26477633-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.2315+16C>T		intron_variant		ENST00000272371.7
OTOF	NM_194323.3	c.74+16C>T		intron_variant		ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.2315+16C>T		intron_variant		1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.74+16C>T		intron_variant		1	NM_194323.3

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 5145 AN: 151976 Hom.: 274 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.0240

GnomAD3 exomes AF: 0.00913 AC: 2250 AN: 246546 Hom.: 112 AF XY: 0.00688 AC XY: 924 AN XY: 134344

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.00578

Gnomad ASJ exome AF: 0.00222

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00245

Gnomad FIN exome AF: 0.0000473

Gnomad NFE exome AF: 0.000741

Gnomad OTH exome AF: 0.00431

GnomAD4 exome AF: 0.00400 AC: 5831 AN: 1459574 Hom.: 255 Cov.: 34 AF XY: 0.00351 AC XY: 2549 AN XY: 726106

Gnomad4 AFR exome AF: 0.120

Gnomad4 AMR exome AF: 0.00664

Gnomad4 ASJ exome AF: 0.00191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00273

Gnomad4 FIN exome AF: 0.0000388

Gnomad4 NFE exome AF: 0.000607

Gnomad4 OTH exome AF: 0.00850

GnomAD4 genome AF: 0.0340 AC: 5166 AN: 152094 Hom.: 275 Cov.: 32 AF XY: 0.0326 AC XY: 2424 AN XY: 74350

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.0148

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.0168 Hom.: 18

Bravo AF: 0.0385

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.43
Dann	Benign	0.69

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: rs73920286; hg19: chr2-26700501;