rs761253981

chr2-26489199-G-Achr2-26489199-G-Cchr2-26489199-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_194248.3(OTOF):c.1045+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000476 in 1,596,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: OTOF NM_194248.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.497

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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-26489199-G-A is Benign according to our data. Variant chr2-26489199-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 263078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.1045+12C>T		intron_variant		ENST00000272371.7
OTOF	NM_001287489.2	c.1045+12C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.1045+12C>T		intron_variant		1	NM_194248.3	A1
OTOF	ENST00000403946.7	c.1045+12C>T		intron_variant		5		P4

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000829 AC: 20 AN: 241170 Hom.: 0 AF XY: 0.0000994 AC XY: 13 AN XY: 130732

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000235

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000922

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000457 AC: 66 AN: 1444078 Hom.: 0 Cov.: 30 AF XY: 0.0000445 AC XY: 32 AN XY: 718692

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000236

Gnomad4 FIN exome AF: 0.0000193

Gnomad4 NFE exome AF: 0.0000464

Gnomad4 OTH exome AF: 0.0000669

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000708 Hom.: 0

Bravo AF: 0.0000604

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	4.9
Dann	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs761253981; hg19: chr2-26712067; COSMIC: COSV55495103;