2-26470685-CCTTCTT-CCTT
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
Consequence
NM_194248.3 conservative_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
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: 68AN: 151962Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.000552 AC: 798AN: 1445854Hom.: 1 AF XY: 0.000513 AC XY: 369AN XY: 719786
GnomAD4 genome AF: 0.000447 AC: 68AN: 152076Hom.: 0 Cov.: 33 AF XY: 0.000377 AC XY: 28AN XY: 74334
ClinVar
Submissions by phenotype
not provided Uncertain:3
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 -
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. -
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
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
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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at