rs397515610

Variant names:

• chr2-26502301-G-A
• rs397515610
• NM_194248.3:c.709C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-26502301-G-A
• chr2-26502301-G-C
• chr2-26502301-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_194248.3(OTOF):​c.709C>T​(p.Arg237*) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.0000144 in 1,461,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: OTOF NM_194248.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.03273
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 4.62

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-26502301-G-A is Pathogenic according to our data. Variant chr2-26502301-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 65814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26502301-G-A is described in Lovd as [Pathogenic]. Variant chr2-26502301-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.709C>T	p.Arg237*	stop_gained, splice_region_variant	Exon 7 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2	c.709C>T	p.Arg237*	stop_gained, splice_region_variant	Exon 7 of 46		NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.709C>T	p.Arg237*	stop_gained, splice_region_variant	Exon 7 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000403946.7	c.709C>T	p.Arg237*	stop_gained, splice_region_variant	Exon 7 of 46	5		ENSP00000385255.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251142 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461656 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jul 29, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified with a second OTOF variant in additional unrelated patients with sensorineural hearing loss in published literature (PMID: 35982127); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 20301429, 37679651, 36056583, 11483641, 38027523, 35982127) -

Jun 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 65814). This premature translational stop signal has been observed in individual(s) with nonsyndromic sensorineural hearing loss (PMID: 11483641). This variant is present in population databases (rs397515610, gnomAD 0.009%). This sequence change creates a premature translational stop signal (p.Arg237*) in the OTOF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOF are known to be pathogenic (PMID: 18381613, 19250381, 22575033). -

Autosomal recessive nonsyndromic hearing loss 9 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.92	D
Vest4		0.88
GERP RS		2.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.033
dbscSNV1_RF	Benign	0.40
SpliceAI score (max)		0.020		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: rs397515610; hg19: chr2-26725169;