2-26462182-C-T

Position:

• chr2-26462182-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_194248.3(OTOF):​c.5193-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000684 in 1,461,626 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 predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: OTOF NM_194248.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 6.18

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.016349683 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-26462182-C-T is Pathogenic according to our data. Variant chr2-26462182-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48256.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.5193-1G>A		splice_acceptor_variant, intron_variant		ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.2892-1G>A		splice_acceptor_variant, intron_variant		ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.5193-1G>A		splice_acceptor_variant, intron_variant		1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.2892-1G>A		splice_acceptor_variant, intron_variant		1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461626 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727126

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Nonsyndromic genetic hearing loss Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Sep 24, 2024

The c.5193-1G>A variant in OTOF occurs within the canonical splice site (+/- 1,2) of exon 42/47 and is predicted to cause altered splicing. Exon 42 is in frame and exon skipping would result in loss of <10% of the OTOF protein, but LOF variants in this region are rare in the general population (PVS1_Moderate). Another variant affecting this splice acceptor site is classified as pathogenic in ClinVar by 1 laboratory (ClinVar Variation ID 2982202, SCV004642429.1). This variant has been observed in 1/1613896 of the total chromosomes in gnomAD v4, with the highest population minor allele frequency in gnomAD v4 is 0.0016% (1/62502 alleles) in the “Remaining” population, which is lower than the ClinGen Hearing Loss VCEP threshold (0.007%) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in 2 patients with hearing loss and auditory neuropathy spectrum disorder (ANSD). In both individuals, this variant was observed with a second likely pathogenic variant, but phase was not determined (1 point, PM3, PP4; PMID: 33111345, Partners LMM internal data SCV000065263.6). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1_Moderate, PM3, PP4, PM2_Supporting. (ClinGen Hearing Loss VCEP specifications version 1; 9/24/2024). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 07, 2022

This sequence change affects an acceptor splice site in intron 41 of the OTOF gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in OTOF are known to be pathogenic (PMID: 18381613, 19250381, 22575033). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 48256). Disruption of this splice site has been observed in individual(s) with autosomal recessive deafness (PMID: 33111345). This variant is not present in population databases (gnomAD no frequency). -

Autosomal recessive nonsyndromic hearing loss 9 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 06, 2022

- -

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
GERP RS		4.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.96		Position offset: -2
DS_AL_spliceai		0.98		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs111033373; hg19: chr2-26685050;