NM_000444.6:c.2239C>T

Variant names:

• chrX-22247942-C-T
• rs886041227
• NM_000444.6:c.2239C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000444.6(PHEX):​c.2239C>T​(p.Arg747*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000924 in 1,082,726 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: PHEX NM_000444.6 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 2.06
• Publications: 11 publications found

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-22247942-C-T is Pathogenic according to our data. Variant chrX-22247942-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 279873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHEX	NM_000444.6	c.2239C>T	p.Arg747*	stop_gained	Exon 22 of 22	ENST00000379374.5	NP_000435.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHEX	ENST00000379374.5	c.2239C>T	p.Arg747*	stop_gained	Exon 22 of 22	1	NM_000444.6	ENSP00000368682.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.24e-7 AC: 1 AN: 1082726 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 348838

African (AFR) AF: 0.0000382 AC: 1 AN: 26146

American (AMR) AF: 0.00 AC: 0 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19301

East Asian (EAS) AF: 0.00 AC: 0 AN: 30146

South Asian (SAS) AF: 0.00 AC: 0 AN: 53766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4101

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 827974

Other (OTH) AF: 0.00 AC: 0 AN: 45583

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Aug 28, 2019

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A hemizygous nonsense variant was identified NM_000444.5(PHEX):c.2239C>T in exon 22 of 22 of the PHEX gene. This nonsense variant is predicted to create a change of arginine to a stop at amino acid position 747 of the protein, NP_000435.3(PHEX):p.(Arg747*), resulting in the loss of normal protein function through truncation. The variant is not present in the gnomAD population database. The variant has previously been reported as pathogenic and segregated with disease in multiple families with X-linked dominant hypophosphatemic rickets (ClinVar, Francis, F. et al. (1997), Holm, I. et al. (2001), Capelli, S. et al. (2015), Acar, S. et al. (2018)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. -

Jan 12, 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

- -

Oct 28, 2013

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:4

Dec 07, 2017

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 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.Arg747*) in the PHEX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 3 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 individuals with X-linked dominant hypophosphatemic rickets (PMID: 9199930, 9768674). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 279873). For these reasons, this variant has been classified as Pathogenic. -

Jan 14, 2022

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 3 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25894638, 24926462, 29505567, 9768674, 9199930, 26051471, 10439971, 11502829, 16055933, 21902834, 30607568, 30682568, 32253725, 32329911, 33666701, 34141703) -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant hypophosphatemic rickets Pathogenic:1

Apr 10, 2022

DASA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2239C>T;p.(Arg747*) variant creates a premature translational stop signal in the PHEX gene without sufficient information about prediction of nonsense mediated mRNA decay (NMD) type change; it is present in a relevant exon to the transcript, and disrupts <10% of the protein product - PVS1_moderate.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 32329911)PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 279873; PMID: 21902834; 19219621; 16055933; 10439971) - PS4. This variant is not present in population databases (rs886041227- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br) - PM2. In summary, the currently available evidence indicates that the variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		2.1
Vest4		0.68
GERP RS		3.9
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs886041227; hg19: chrX-22266059; COSMIC: COSV65073821;