rs1060501124
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_003924.4(PHOX2B):āc.730G>Cā(p.Ala244Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,168,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_003924.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PHOX2B | NM_003924.4 | c.730G>C | p.Ala244Pro | missense_variant | 3/3 | ENST00000226382.4 | NP_003915.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PHOX2B | ENST00000226382.4 | c.730G>C | p.Ala244Pro | missense_variant | 3/3 | 1 | NM_003924.4 | ENSP00000226382.2 | ||
PHOX2B | ENST00000510424.2 | n.*11G>C | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000135 AC: 2AN: 147616Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000196 AC: 2AN: 1020706Hom.: 0 Cov.: 31 AF XY: 0.00000206 AC XY: 1AN XY: 486436
GnomAD4 genome AF: 0.0000135 AC: 2AN: 147616Hom.: 0 Cov.: 32 AF XY: 0.0000139 AC XY: 1AN XY: 71908
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | May 26, 2023 | - - |
Haddad syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 24, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 244 of the PHOX2B protein (p.Ala244Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PHOX2B-related conditions. ClinVar contains an entry for this variant (Variation ID: 406409). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PHOX2B protein function. 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 provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 29, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 11, 2024 | The p.A244P variant (also known as c.730G>C), located in coding exon 3 of the PHOX2B gene, results from a G to C substitution at nucleotide position 730. The alanine at codon 244 is replaced by proline, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at