NM_000444.6:c.2104C>T

Variant names:

• chrX-22245366-C-T
• rs886041226
• NM_000444.6:c.2104C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000444.6(PHEX):​c.2104C>T​(p.Arg702*) 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 NM_000444.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.910

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

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0649 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-22245366-C-T is Pathogenic according to our data. Variant chrX-22245366-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 279872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-22245366-C-T is described in Lovd as [Pathogenic]. Variant chrX-22245366-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHEX	NM_000444.6	c.2104C>T	p.Arg702*	stop_gained	Exon 21 of 22	ENST00000379374.5	NP_000435.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHEX	ENST00000379374.5	c.2104C>T	p.Arg702*	stop_gained	Exon 21 of 22	1	NM_000444.6	ENSP00000368682.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial X-linked hypophosphatemic vitamin D refractory rickets Pathogenic:3

Oct 07, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 12, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PVS1_Strong+PS4+PM6_Strong -

not provided Pathogenic:3

Oct 04, 2018

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg702*) in the PHEX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acid(s) of the PHEX protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hypophosphatemic rickets (PMID: 9097956, 9768674, 21902834, 23079138, 29505567). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 279872). For these reasons, this variant has been classified as Pathogenic. -

Dec 23, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 48 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Reported in multiple unrelated individuals with hypophosphatemic rickets (Rowe et al., 1997; Holm et al., 2001; Zivicnjak et al., 2011; Morey et al., 2011; Cheon et al., 2014; Zhang et al., 2015; Acar et al., 2018; Lin et al., 2020; Thiele et al., 2020); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25894638, 16636593, 9768674, 32253725, 24926462, 26377240, 11502829, 23079138, 19219621, 21994957, 21902834, 29505567, 30682568, 33107440, 34434907, 34141703, 9097956) -

PHEX-related disorder Pathogenic:1

Nov 22, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PHEX c.2104C>T variant is predicted to result in premature protein termination (p.Arg702*). This variant was reported to be pathogenic for X-linked hypophosphataemic rickets (see examples: Rowe et al 1997. PubMed ID: 9097956; Figure 3A, Zhang et al 2019. PubMed ID: 30682568; Table S1, Park et al 2021. PubMed ID: 34434907). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in PHEX are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.86	D
Vest4		0.85
GERP RS		-0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs886041226; hg19: chrX-22263483;