rs886041319
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_181458.4(PAX3):c.784C>T(p.Arg262Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
PAX3
NM_181458.4 stop_gained
NM_181458.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.54
Genes affected
PAX3 (HGNC:8617): (paired box 3) This gene is a member of the paired box (PAX) family of transcription factors. Members of the PAX family typically contain a paired box domain and a paired-type homeodomain. These genes play critical roles during fetal development. Mutations in paired box gene 3 are associated with Waardenburg syndrome, craniofacial-deafness-hand syndrome, and alveolar rhabdomyosarcoma. The translocation t(2;13)(q35;q14), which represents a fusion between PAX3 and the forkhead gene, is a frequent finding in alveolar rhabdomyosarcoma. Alternative splicing results in transcripts encoding isoforms with different C-termini. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-222232086-G-A is Pathogenic according to our data. Variant chr2-222232086-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 280007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-222232086-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAX3 | NM_181458.4 | c.784C>T | p.Arg262Ter | stop_gained | 5/9 | ENST00000392070.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAX3 | ENST00000392070.7 | c.784C>T | p.Arg262Ter | stop_gained | 5/9 | 1 | NM_181458.4 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Waardenburg syndrome type 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital | Jan 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 07, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 280007). This premature translational stop signal has been observed in individual(s) with clinical features of Waardenburg syndrome (PMID: 23512835, 27759048). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg262*) in the PAX3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAX3 are known to be pathogenic (PMID: 20127975, 23512835). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 29, 2018 | The R262X variant in the PAX3 gene has been reported previously in multiple individuals with Waardenburg syndrome type 1 (Wildhardt et al., 2013; Jalilian et al., 2015). It has also been confirmed at GeneDx to have occurred de novo in an affected patient. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is not observed in large population cohorts (Lek et al., 2016). We consider this variant to be pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A;A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at