rs111033425
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_194248.3(OTOF):c.4822G>T(p.Asp1608Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000065 in 1,492,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D1608D) has been classified as Likely benign.
Frequency
Consequence
NM_194248.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOF | NM_194248.3 | c.4822G>T | p.Asp1608Tyr | missense_variant | 39/47 | ENST00000272371.7 | |
OTOF | NM_194323.3 | c.2521G>T | p.Asp841Tyr | missense_variant | 22/29 | ENST00000339598.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.4822G>T | p.Asp1608Tyr | missense_variant | 39/47 | 1 | NM_194248.3 | A1 | |
OTOF | ENST00000339598.8 | c.2521G>T | p.Asp841Tyr | missense_variant | 22/29 | 1 | NM_194323.3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152072Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000102 AC: 18AN: 177074Hom.: 0 AF XY: 0.000106 AC XY: 10AN XY: 94112
GnomAD4 exome AF: 0.0000694 AC: 93AN: 1339874Hom.: 0 Cov.: 31 AF XY: 0.0000870 AC XY: 57AN XY: 655138
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152190Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74392
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 19, 2021 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 24, 2021 | This sequence change replaces aspartic acid with tyrosine at codon 1608 of the OTOF protein (p.Asp1608Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs111033425, ExAC 0.1%). This variant has not been reported in the literature in individuals with OTOF-related conditions. ClinVar contains an entry for this variant (Variation ID: 48241). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 26, 2009 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 06, 2022 | The c.4822G>T (p.D1608Y) alteration is located in exon 39 (coding exon 39) of the OTOF gene. This alteration results from a G to T substitution at nucleotide position 4822, causing the aspartic acid (D) at amino acid position 1608 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at