rs775006915
Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2
The NM_003924.4(PHOX2B):βc.741_755delβ(p.Ala256_Ala260del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00474 in 1,204,798 control chromosomes in the GnomAD database, including 44 homozygotes. Variant has been reported in ClinVar as Likely benign (β β ). Synonymous variant affecting the same amino acid position (i.e. A247A) has been classified as Likely benign.
Frequency
Consequence
NM_003924.4 inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PHOX2B | NM_003924.4 | c.741_755del | p.Ala256_Ala260del | inframe_deletion | 3/3 | ENST00000226382.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PHOX2B | ENST00000226382.4 | c.741_755del | p.Ala256_Ala260del | inframe_deletion | 3/3 | 1 | NM_003924.4 | P1 | |
PHOX2B | ENST00000510424.2 | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00330 AC: 484AN: 146522Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00324 AC: 42AN: 12966Hom.: 0 AF XY: 0.00285 AC XY: 22AN XY: 7732
GnomAD4 exome AF: 0.00494 AC: 5228AN: 1058178Hom.: 43 AF XY: 0.00491 AC XY: 2485AN XY: 505948
GnomAD4 genome ? AF: 0.00330 AC: 484AN: 146620Hom.: 1 Cov.: 32 AF XY: 0.00334 AC XY: 238AN XY: 71322
ClinVar
Submissions by phenotype
not specified Benign:5
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 14, 2016 | p.Ala256_Ala260del (also known as p.Ala241[15]) in exon 3 of PHOX2B: This varian t is common in the general population and therefore believed to be benign (Gener eviews: www.ncbi.nlm.nih.gov/books/NBK1427/#ondine.Molecular_Genetics). It was d etected in 2% (63/3266) of East Asian chromosomes, including 2 homozygotes, by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs7 75006915). This variant represents a deletion of 5 alanine amino acids within a repeat sequence in this gene, for a total of 15 total repeats (The predominant n ormal allele contains 20 repeats). - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 17, 2014 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 11, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 14, 2023 | Variant summary: PHOX2B c.741_755del15 (p.Ala256_Ala260del) results in an in-frame deletion that is predicted to remove 5 amino acids from the encoded protein. This variant is located to a poly-alanine repeat region, where the major allele contains a 20 alanine stretch, and this variant removes 5 alanines. The variant allele was found at a frequency of 0.0033 in 145318 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 4000-fold of the estimated maximal expected allele frequency for a pathogenic variant in PHOX2B causing Neuroblastoma, Susceptibility Type, 2 phenotype (8.3e-07), strongly suggesting that the variant is benign. The variant, c.741_755del15 or equivalent protein level changes, have been reported in the literature in individuals affected with Neuroblastoma (e.g. Raabe_2008), however without providing evidence for causality. Similar 5 alanine deletion variants have also been reported in patients affected with Hirschsprung disease, with some of them noting mild neonatal respiratory disorders (Di Zanni_2017). Authors of this study also reported experimental evidence evaluating the impact of contractions of the polyalanine tract, and demonstrated that the -5Ala variant resulted in ~95% transactivation response compared to the WT on RET promoter, while greater contractions (-7Ala and -13Ala) resulted in significantly lower transactivation values (Di Zanni_2017), therefore authors of this study proposed that contractions of the 20 alanine stretch of the PHOX2B gene could increase the susceptibility to Hirschsprung disease (with mild neonatal respiratory disorders). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
not provided Benign:5
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 06, 2020 | This variant is associated with the following publications: (PMID: 17637745, 14566559) - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | PHOX2B: BS1 - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 31, 2019 | 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. - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 26, 2020 | - - |
Haddad syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at