4-41746255-G-A
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_003924.4(PHOX2B):c.497C>T(p.Ala166Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,120 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A166E) has been classified as Uncertain significance.
Frequency
Consequence
NM_003924.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PHOX2B | NM_003924.4 | c.497C>T | p.Ala166Val | missense_variant | 3/3 | ENST00000226382.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PHOX2B | ENST00000226382.4 | c.497C>T | p.Ala166Val | missense_variant | 3/3 | 1 | NM_003924.4 | P1 | |
PHOX2B | ENST00000510424.2 | n.318C>T | non_coding_transcript_exon_variant | 3/3 | 3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000815 AC: 2AN: 245510Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 133976
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461120Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726924
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Haddad syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 28, 2021 | 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. This variant has not been reported in the literature in individuals with PHOX2B-related disease. This variant is present in population databases (rs774521395, ExAC 0.006%). This sequence change replaces alanine with valine at codon 166 of the PHOX2B protein (p.Ala166Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 08, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at