chrX-22090443-ACT-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000444.6(PHEX):c.682_683del(p.Ser228ProfsTer9) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 23)
Consequence
PHEX
NM_000444.6 frameshift
NM_000444.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.09
Genes affected
PHEX (HGNC:8918): (phosphate regulating endopeptidase X-linked) The protein encoded by this gene is a transmembrane endopeptidase that belongs to the type II integral membrane zinc-dependent endopeptidase family. The protein is thought to be involved in bone and dentin mineralization and renal phosphate reabsorption. Mutations in this gene cause X-linked hypophosphatemic rickets. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-22090443-ACT-A is Pathogenic according to our data. Variant chrX-22090443-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 419563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-22090443-ACT-A is described in Lovd as [Pathogenic]. Variant chrX-22090443-ACT-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PHEX | NM_000444.6 | c.682_683del | p.Ser228ProfsTer9 | frameshift_variant | 6/22 | ENST00000379374.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PHEX | ENST00000379374.5 | c.682_683del | p.Ser228ProfsTer9 | frameshift_variant | 6/22 | 1 | NM_000444.6 | P1 | |
PHEX | ENST00000684143.1 | c.679_680del | p.Ser227ProfsTer9 | frameshift_variant | 6/11 | ||||
PHEX | ENST00000475778.2 | n.1108_1109del | non_coding_transcript_exon_variant | 6/9 | 5 | ||||
PHEX | ENST00000684745.1 | n.356_357del | non_coding_transcript_exon_variant | 4/20 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial X-linked hypophosphatemic vitamin D refractory rickets Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1995 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Oct 28, 2013 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 12, 2015 | The c.682_683delTC deletion in the PHEX gene has been reported previously in association with X-Linked hypophosphatemic rickets (Francis et al., 1995). The deletion causes a frameshift starting with codon Serine 228, changes this amino acid to a Proline residue and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Ser228ProfsX9. This deletion is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, we interpret the c.682_683delTC variant as pathogenic. - |
Computational scores
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Calibrated prediction
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at