rs767837376
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_ModerateBS2
The NM_003924.4(PHOX2B):c.487G>T(p.Ala163Ser) 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 1,460,136 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A163T) has been classified as Uncertain significance.
Frequency
Consequence
NM_003924.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PHOX2B | NM_003924.4 | c.487G>T | p.Ala163Ser | missense_variant | 3/3 | ENST00000226382.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PHOX2B | ENST00000226382.4 | c.487G>T | p.Ala163Ser | missense_variant | 3/3 | 1 | NM_003924.4 | P1 | |
PHOX2B | ENST00000510424.2 | n.308G>T | non_coding_transcript_exon_variant | 3/3 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000410 AC: 1AN: 243994Hom.: 0 AF XY: 0.00000750 AC XY: 1AN XY: 133352
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460136Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 726444
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Haddad syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 12, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 163 of the PHOX2B protein (p.Ala163Ser). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 535767). 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 04, 2022 | The p.A163S variant (also known as c.487G>T), located in coding exon 3 of the PHOX2B gene, results from a G to T substitution at nucleotide position 487. The alanine at codon 163 is replaced by serine, an amino acid with 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