rs199560470
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3BP4_ModerateBP6BS1
The NM_181458.4(PAX3):āc.572T>Cā(p.Ile191Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,614,206 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I191F) has been classified as Uncertain significance.
Frequency
Consequence
NM_181458.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAX3 | NM_181458.4 | c.572T>C | p.Ile191Thr | missense_variant | 4/9 | ENST00000392070.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAX3 | ENST00000392070.7 | c.572T>C | p.Ile191Thr | missense_variant | 4/9 | 1 | NM_181458.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000366 AC: 92AN: 251492Hom.: 0 AF XY: 0.000368 AC XY: 50AN XY: 135922
GnomAD4 exome AF: 0.0000677 AC: 99AN: 1461894Hom.: 1 Cov.: 35 AF XY: 0.0000715 AC XY: 52AN XY: 727248
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152312Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74480
ClinVar
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 01, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 18, 2020 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 28, 2017 | Variant classified as Uncertain Significance - Favor Benign. The p.Ile191Thr var iant in PAX3 has been previously reported by our laboratory in one Hispanic indi vidual with hearing loss, but it has also been identified in 0.26% (89/33582) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.br oadinstitute.org/; dbSNP rs199560470). Although this variant has been seen in th e general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enoug h to determine pathogenicity. In summary, while the clinical significance of the p.Ile191Thr variant is uncertain, the frequency data in the general population suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1, PP3 (Richards 2015). - |
PAX3-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 09, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at