rs747713899

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_003924.4(PHOX2B):​c.667G>T​(p.Ala223Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,378,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

PHOX2B
NM_003924.4 missense

Scores

1
1
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.245
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0630852).
BP6
Variant 4-41746085-C-A is Benign according to our data. Variant chr4-41746085-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 535765.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PHOX2BNM_003924.4 linkuse as main transcriptc.667G>T p.Ala223Ser missense_variant 3/3 ENST00000226382.4 NP_003915.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PHOX2BENST00000226382.4 linkuse as main transcriptc.667G>T p.Ala223Ser missense_variant 3/31 NM_003924.4 ENSP00000226382 P1
PHOX2BENST00000510424.2 linkuse as main transcriptn.488G>T non_coding_transcript_exon_variant 3/33

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000111
AC:
2
AN:
179994
Hom.:
0
AF XY:
0.00000981
AC XY:
1
AN XY:
101950
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000759
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000145
AC:
2
AN:
1378126
Hom.:
0
Cov.:
31
AF XY:
0.00000146
AC XY:
1
AN XY:
684980
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000535
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.00000849
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Haddad syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 26, 2020In 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PHOX2B-related conditions. ClinVar contains an entry for this variant (Variation ID: 535765). This variant is present in population databases (rs747713899, ExAC 0.02%). This sequence change replaces alanine with serine at codon 223 of the PHOX2B protein (p.Ala223Ser). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and serine. -
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 29, 2023This alteration is classified as 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.067
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
7.8
DANN
Benign
0.64
DEOGEN2
Benign
0.19
T
Eigen
Benign
-0.76
Eigen_PC
Benign
-0.81
FATHMM_MKL
Benign
0.54
D
LIST_S2
Benign
0.44
T
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.063
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.55
N
MutationTaster
Benign
1.0
N
PrimateAI
Pathogenic
0.85
D
PROVEAN
Benign
0.17
N
REVEL
Benign
0.15
Sift
Benign
0.52
T
Sift4G
Benign
0.88
T
Polyphen
0.0020
B
Vest4
0.13
MutPred
0.31
Gain of phosphorylation at A223 (P = 0.003);
MVP
0.57
MPC
1.0
ClinPred
0.024
T
GERP RS
2.4
Varity_R
0.045
gMVP
0.43

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs747713899; hg19: chr4-41748102; COSMIC: COSV56929830; COSMIC: COSV56929830; API