2-26470685-CCTTCTT-CCTT

Variant names:

• chr2-26470685-CCTT-C
• rs368148603
• NM_194248.3:c.3928_3930delAAG

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_194248.3(OTOF):​c.3928_3930delAAG​(p.Lys1310del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000542 in 1,597,930 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00055 (1 hom.)
• Consequence: OTOF NM_194248.3 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 4.74

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.3928_3930delAAG	p.Lys1310del	conservative_inframe_deletion	Exon 32 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.1627_1629delAAG	p.Lys543del	conservative_inframe_deletion	Exon 15 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.3928_3930delAAG	p.Lys1310del	conservative_inframe_deletion	Exon 32 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.1627_1629delAAG	p.Lys543del	conservative_inframe_deletion	Exon 15 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 151962 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000530

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000552 AC: 798 AN: 1445854 Hom.: 1 AF XY: 0.000513 AC XY: 369 AN XY: 719786

Gnomad4 AFR exome AF: 0.000574

Gnomad4 AMR exome AF: 0.000247

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.000280

Gnomad4 SAS exome AF: 0.000338

Gnomad4 FIN exome AF: 0.000626

Gnomad4 NFE exome AF: 0.000602

Gnomad4 OTH exome AF: 0.000469

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152076 Hom.: 0 Cov.: 33 AF XY: 0.000377 AC XY: 28 AN XY: 74334

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.000530

Gnomad4 OTH AF: 0.000473

Bravo AF: 0.000408

EpiCase AF: 0.000548

EpiControl AF: 0.000595

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2024	In-frame deletion of 1 amino acid in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports a deleterious effect on protein structure/function -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 05, 2022	This variant, c.3928_3930del, results in the deletion of 1 amino acid(s) of the OTOF protein (p.Lys1310del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with deafness (Invitae). ClinVar contains an entry for this variant (Variation ID: 229078). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The OTOF p.Lys620del variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs759676287) and ClinVar (classified as a VUS by Laboratory for Molecular Medicine). The variant was identified in control databases in 155 of 279488 chromosomes (0 homozygous) at a frequency of 0.0005546 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 28 of 24002 chromosomes (freq: 0.001167), Other in 7 of 7168 chromosomes (freq: 0.000977), African in 17 of 24838 chromosomes (freq: 0.000684), European (non-Finnish) in 80 of 127520 chromosomes (freq: 0.000627), South Asian in 8 of 30524 chromosomes (freq: 0.000262), Latino in 9 of 35282 chromosomes (freq: 0.000255), East Asian in 4 of 19872 chromosomes (freq: 0.000201), and Ashkenazi Jewish in 2 of 10282 chromosomes (freq: 0.000195). This variant is an in-frame deletion resulting in the removal of a lysine (lys) residue at codon 620; the impact of this alteration on OTOF protein function is not known. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 12, 2015

The p.Lys1310del variant in OTOF has not been previously reported in individuals with hearing loss, but has been identified in 0.1% (10/10350) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org) . This variant is predicted to lead to a deletion of a lysine residue at positio n 1310 in a poly-lysine tract and not to alter the protein reading-frame. It is unclear whether this deletion will impact the protein. In summary, the clinical significance of the p.Lys1310del variant is uncertain. -

OTOF-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 22, 2024

The OTOF c.3928_3930delAAG variant is predicted to result in an in-frame deletion (p.Lys1310del). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.12% of alleles in individuals of European (Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Autosomal recessive nonsyndromic hearing loss 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

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: rs368148603; hg19: chr2-26693553;