dbSNP rs866429868: PHEX:p.Arg291* (chrX-22096976-C-T) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000444.6(PHEX):c.871C>T(p.Arg291*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

PHEX
NM_000444.6 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 1.79

Variant links:

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]

PHEX links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant X-22096976-C-T is Pathogenic according to our data. Variant chrX-22096976-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 372454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-22096976-C-T is described in Lovd as [Pathogenic]. Variant chrX-22096976-C-T is described in Lovd as [Pathogenic]. Variant chrX-22096976-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHEX	NM_000444.6 link	c.871C>T	p.Arg291*	stop_gained	Exon 8 of 22	ENST00000379374.5	NP_000435.3	P78562B4DWG8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PHEX	ENST00000379374.5 link	c.871C>T	p.Arg291*	stop_gained	Exon 8 of 22	1	NM_000444.6	ENSP00000368682.4	P78562
PHEX	ENST00000684143.1 link	c.868C>T	p.Arg290*	stop_gained	Exon 8 of 11			ENSP00000508264.1	A0A804HLA0
PHEX	ENST00000475778.2 link	n.1297C>T		non_coding_transcript_exon_variant	Exon 8 of 9	5
PHEX	ENST00000684745.1 link	n.545C>T		non_coding_transcript_exon_variant	Exon 6 of 20

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

111127

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33449

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1090055

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

356019

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

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0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

111127

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33449

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000104

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial X-linked hypophosphatemic vitamin D refractory rickets

Pathogenic:5

May 31, 2019

Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 08, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in PHEX is a nonsense variant predicted to create a premature stop codon, p.(Arg291*), in biologically relevant exon 8/22 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 22319799). Loss-of-function variants are a well-established cause of disease in exon 8 (ClinVar). This variant is absent from the population database gnomAD v4.1. This variant has been reported in multiple individuals with hypophosphataemia and segregates with hypophosphataemia in two unrelated families (PMID: 34633109, 11004247, 11502829). This variant has also been identified as a de novo occurrence with confirmed parental relationships in an individual and as a de novo occurrence with unconfirmed parental relationships in another individual with hypophosphataemic rickets (PMID: 36482408, 32329911). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PS4, PM2_Supporting, PM5_Supporting, PS2_Moderate/PM6 -

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

- -

Apr 17, 2015

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Dec 12, 2024

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.Arg291*) 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 individual(s) with hypophosphatemic rickets (PMID: 9106524, 11004247, 23466123, 26040324, 29460029, 30298486). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372454). For these reasons, this variant has been classified as Pathogenic. -

Mar 18, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 9106524, 26040324, 23466123, 11004247, 27840894, 11502829, 29460029, 19219621, 9199930, 30607568, 30682568, 30298486, 29707405, 34434907, 33639975, 32329911, 34006472, 34141703, 33537138) -

Jul 10, 2019

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 result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. -

Hypophosphatemic rickets

Pathogenic:1

Mar 07, 2022

Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

FATHMM_MKL

Uncertain

0.88

Vest4

0.95

GERP RS

5.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over