2-26464907-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_194248.3(OTOF):c.4922G>A(p.Arg1641His) variant causes a missense change. The variant allele was found at a frequency of 0.0000482 in 1,597,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1641R) has been classified as Likely benign.
Frequency
Consequence
NM_194248.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOF | NM_194248.3 | c.4922G>A | p.Arg1641His | missense_variant | 39/47 | ENST00000272371.7 | |
OTOF | NM_194323.3 | c.2621G>A | p.Arg874His | missense_variant | 22/29 | ENST00000339598.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.4922G>A | p.Arg1641His | missense_variant | 39/47 | 1 | NM_194248.3 | A1 | |
OTOF | ENST00000339598.8 | c.2621G>A | p.Arg874His | missense_variant | 22/29 | 1 | NM_194323.3 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152140Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000203 AC: 49AN: 240798Hom.: 0 AF XY: 0.000169 AC XY: 22AN XY: 130274
GnomAD4 exome AF: 0.0000477 AC: 69AN: 1445212Hom.: 0 Cov.: 31 AF XY: 0.0000376 AC XY: 27AN XY: 718118
GnomAD4 genome AF: 0.0000525 AC: 8AN: 152258Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74438
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 19, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 23, 2023 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 04, 2014 | Variant classified as Uncertain Significance - Favor Benign. The Arg1641His vari ant in OTOF has been previously identified two Hispanic individuals with hearing loss and one affected sibling by our laboratory However, none of these individu als carried a second variant in the OTOF gene. In addition, the Arg1641His varia nt been identified in 0.8% (1/128) of Mexican chromosomes by the 1000Genomes pro ject (dbSNP rs200283244). Computational prediction tools and conservation analys es suggest that the Arg1641His variant may not impact the protein, though this i nformation is not predictive enough to rule out pathogenicity. Of note, two mamm als, walrus and panda, also carry a histidine (His) at this position. In summary , the clinical significance of this variant cannot be determined with certainty; however, based upon the absence of a second OTOF variant in affected individual s, its presence in the general population, and the lack of conservation at the A rg1641 position, we would lean towards a more likely benign role. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at