rs199992845
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_194248.3(OTOF):c.154G>A(p.Val52Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,613,870 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V52V) 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOF | NM_194248.3 | c.154G>A | p.Val52Met | missense_variant | 3/47 | ENST00000272371.7 | |
OTOF | NM_001287489.2 | c.154G>A | p.Val52Met | missense_variant | 3/46 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.154G>A | p.Val52Met | missense_variant | 3/47 | 1 | NM_194248.3 | A1 | |
OTOF | ENST00000403946.7 | c.154G>A | p.Val52Met | missense_variant | 3/46 | 5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000256 AC: 39AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000278 AC: 70AN: 251410Hom.: 0 AF XY: 0.000265 AC XY: 36AN XY: 135904
GnomAD4 exome AF: 0.000235 AC: 344AN: 1461580Hom.: 1 Cov.: 32 AF XY: 0.000234 AC XY: 170AN XY: 727120
GnomAD4 genome ? AF: 0.000256 AC: 39AN: 152290Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18AN XY: 74464
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 9 Uncertain:2
Uncertain significance, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | May 23, 2015 | Tne heterozygous variant was identified in the OTOF gene (c.154G>A; p.Val52Met) is considered a variant of uncertain significance. This variant has not been previously published in the literature and it is seen in 22 individuals in the ExAC database. Pathogenic mutations in this gene have been associated with autosomal recessive Deafness (MIM: 601071). The call for unknown significance for this variant is due to it's being a rare variant in an amino acid position that is conserved through birds. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 13, 2017 | The p.Val52Met variant in OTOF has been previously reported by our laboratory in 1 individual with hearing loss, but a variant affecting the other copy of the g ene was not identified. This variant has also been reported in ClinVar (Variatio n ID# 164881) as of uncertain significance. The p.Val52Met variant has been iden tified in 28/34420 Latino chromosomes by the Genome Aggregation Database (gnomAD , http://gnomad.broadinstitute.org; dbSNP rs199992845); however its frequency is not high enough to rule out a pathogenic role. Computational prediction tools a nd conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Val52Met variant is uncertain. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at