rs875989883

Variant names:

• chrX-22219070-G-A
• rs875989883
• NM_000444.6:c.1735G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-22219070-G-A
• chrX-22219070-G-C
• chrX-22219070-G-T

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000444.6(PHEX):​c.1735G>A​(p.Gly579Arg) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G579E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PHEX NM_000444.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 8.63

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]

PTCHD1-AS (HGNC:37703): (PTCHD1 antisense RNA (head to head))

ACMG classification

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS1: Transcript NM_000444.6 (PHEX) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 438542
• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000444.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-22219071-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 378359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 135 curated pathogenic missense variants (we use a threshold of 10). The gene has 25 curated benign missense variants. Gene score misZ: 1.7091 (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked dominant hypophosphatemic rickets.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-22219070-G-A is Pathogenic according to our data. Variant chrX-22219070-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-22219070-G-A is described in Lovd as [Pathogenic]. Variant chrX-22219070-G-A is described in Lovd as [Likely_pathogenic]. Variant chrX-22219070-G-A is described in Lovd as [Pathogenic]. Variant chrX-22219070-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHEX	NM_000444.6	c.1735G>A	p.Gly579Arg	missense_variant	Exon 17 of 22	ENST00000379374.5	NP_000435.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHEX	ENST00000379374.5	c.1735G>A	p.Gly579Arg	missense_variant	Exon 17 of 22	1	NM_000444.6	ENSP00000368682.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1072214 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 342346

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 25924

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 35177

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 19201

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 30050

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 53512

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 40367

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 818703

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 45216

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial X-linked hypophosphatemic vitamin D refractory rickets Pathogenic:5

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Pathogenic, for Hypophosphatemic rickets, X-linked dominant, in X-linked Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation found in unrelated patients. (PMID:9199930). PS3 => Well-established functional studies show a deleterious effect (PMID:11468271,12727977). PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:24684036). -

Apr 05, 2016

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The identified PHEX mutation is the likely genetic cause for the hypophosphatemic rickets observed in the patient. -

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000226119,VCV000438542, PS1_S). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M).Different missense changes at the same codon (p.Gly579Val, p.Gly579Glu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000372777,VCV000378359, PMID:9097956, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.931, 3CNET: 0.997, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Oct 28, 2013

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 17, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 579 of the PHEX protein (p.Gly579Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypophosphatemic rickets (PMID: 9097956, 9199930, 18625346, 29858904). ClinVar contains an entry for this variant (Variation ID: 226119). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PHEX protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PHEX function (PMID: 11468271). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Sep 19, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The G579R missense variant in the PHEX gene has been reported previously as de novo and in association with X-linked hypophosphatemic rickets (Rowe et al., 1997; Durmaz et al., 2013; Radlovic et al., 2014). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). G579R is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, another nucelotide change at the same codon (c.1735 G>C) also leading to the G579R missense change, a missense variant in at the same residue (G579V), and missense variants in nearby residues (H580P, F582S, H584P) have all been reported in the Human Gene Mutation Database in association with PHEX-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Furthermore, functional studies of the G579R variant have shown that it results in incomplete glycosylation of the protein leading to failed expression at the plasma membrane and degradation within the endoplasmic reticulum (Sabbagh et al., 2001; Sabbagh et al., 2003). -

Vitamin D-dependent rickets, type 2 Pathogenic:1

Apr 01, 2017

Department of Traditional Chinese Medicine, Fujian Provincial Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.97		Loss of catalytic residue at I577 (P = 0.183);
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.49		Position offset: 33

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

Publications

LitVar

Other links and lift over

dbSNP: rs875989883; hg19: chrX-22237187;