X-22033063-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000379374.5(PHEX):c.58C>T(p.Arg20Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 22)
Consequence
PHEX
ENST00000379374.5 stop_gained
ENST00000379374.5 stop_gained
Scores
2
1
2
Clinical Significance
Conservation
PhyloP100: 1.74
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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 871 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-22033063-C-T is Pathogenic according to our data. Variant chrX-22033063-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 379502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-22033063-C-T is described in Lovd as [Pathogenic]. Variant chrX-22033063-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PHEX | NM_000444.6 | c.58C>T | p.Arg20Ter | stop_gained | 1/22 | ENST00000379374.5 | NP_000435.3 | |
PHEX | NM_001282754.2 | c.58C>T | p.Arg20Ter | stop_gained | 1/21 | NP_001269683.1 | ||
PHEX | XM_047442159.1 | c.58C>T | p.Arg20Ter | stop_gained | 1/13 | XP_047298115.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PHEX | ENST00000379374.5 | c.58C>T | p.Arg20Ter | stop_gained | 1/22 | 1 | NM_000444.6 | ENSP00000368682 | P1 | |
PHEX | ENST00000684143.1 | c.58C>T | p.Arg20Ter | stop_gained | 1/11 | ENSP00000508264 | ||||
PHEX | ENST00000475778.2 | n.484C>T | non_coding_transcript_exon_variant | 1/9 | 5 | |||||
PHEX | ENST00000683214.1 | n.484C>T | non_coding_transcript_exon_variant | 1/2 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD3 genomes
Cov.:
22
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome Cov.: 22
GnomAD4 genome
Cov.:
22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial X-linked hypophosphatemic vitamin D refractory rickets Pathogenic:3
Pathogenic, no assertion criteria provided | research | Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital | May 31, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | Jan 13, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Oct 28, 2013 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 22, 2023 | This sequence change creates a premature translational stop signal (p.Arg20*) in the PHEX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PHEX are known to be pathogenic (PMID: 9097956, 9106524, 19219621). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with X-linked hypophosphatemic rickets (PMID: 9097956, 9199930). ClinVar contains an entry for this variant (Variation ID: 379502). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 04, 2016 | The R20X nonsense variant in the PHEX gene has been frequently reported in association withX-Linked Hypophosphatemic Rickets (Rowe et al., 1997; Francis et al., 1997; Cho et al., 2005). TheR20X variant was not observed in approximately 6,500 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant inthese populations. This pathogenic variant is predicted to cause loss of normal protein function eitherthrough protein truncation or nonsense-mediated mRNA decay. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A
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