rs1553897738
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4
The NM_003924.4(PHOX2B):c.945A>G(p.Ter315TrpextTer41) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
PHOX2B
NM_003924.4 stop_lost
NM_003924.4 stop_lost
Scores
1
2
4
Clinical Significance
Conservation
PhyloP100: 3.35
Genes affected
PHOX2B (HGNC:9143): (paired like homeobox 2B) The DNA-associated protein encoded by this gene is a member of the paired family of homeobox proteins localized to the nucleus. The protein functions as a transcription factor involved in the development of several major noradrenergic neuron populations and the determination of neurotransmitter phenotype. The gene product is linked to enhancement of second messenger-mediated activation of the dopamine beta-hydroylase, c-fos promoters and several enhancers, including cyclic amp-response element and serum-response element. Expansion of a 20 amino acid polyalanine tract in this protein by 5-13 aa has been associated with congenital central hypoventilation syndrome. [provided by RefSeq, Jul 2016]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 4-41745807-T-C is Pathogenic according to our data. Variant chr4-41745807-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 521682.Status of the report is criteria_provided_single_submitter, 1 stars.
BP4
?
Computational evidence support a benign effect (BayesDel_addAF=-0.0672748).. Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PHOX2B | NM_003924.4 | c.945A>G | p.Ter315TrpextTer41 | stop_lost | 3/3 | ENST00000226382.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PHOX2B | ENST00000226382.4 | c.945A>G | p.Ter315TrpextTer41 | stop_lost | 3/3 | 1 | NM_003924.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 06, 2017 | The p.*315Wext*41 pathogenic mutation (also known as c.945A>G), located in coding exon 3 of the PHOX2B gene, results from an A to G substitution at nucleotide position 945, which is the last nucleotide of the PHOX2B gene. The stop codon at position 315 is replaced by tryptophan, resulting in an elongation of the protein by 41 amino acids. This alteration, as well as two other alterations (c.945A>T, c.945A>C), which also change the stop codon and elongate the protein by 41 amino acids (p.*315Cext*41), have been reported in individuals with congenital central hypoventilation syndrome (Weese-Mayer DE et al. Pediatr. Pulmonol., 2009 Jun;44:521-35; Szczapa T et al. J Perinatol, 2013 Nov;33:905-7; Trochet D et al. Am. J. Hum. Genet., 2005 Mar;76:421-6). In addition to the clinical data presented in the literature, this alteration is expected to result in abnormal protein production and is thus interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
N
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