rs886041224

Positions:

• chrX-22190502-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000444.6(PHEX):​c.1645C>T​(p.Arg549*) variant causes a stop gained, splice region 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. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PHEX NM_000444.6 stop_gained, splice_region
• Scores: Splicing: ADA: 0.4789
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.601

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-22190502-C-T is Pathogenic according to our data. Variant chrX-22190502-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 279870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-22190502-C-T is described in Lovd as [Pathogenic]. Variant chrX-22190502-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.1645C>T	p.Arg549*	stop_gained, splice_region_variant	15/22	ENST00000379374.5	NP_000435.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHEX	ENST00000379374.5	c.1645C>T	p.Arg549*	stop_gained, splice_region_variant	15/22	1	NM_000444.6	ENSP00000368682.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1053661 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 324597

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 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 Cov.: 23

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:4

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	May 23, 2023	PVS1, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000279870 / PMID: 9097956). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 19, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Jan 12, 2024	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2019	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 (Lek et al., 2016); This variant is associated with the following publications: (PMID: 16636593, 24836714, 21902834, 19219621, 24926462, 26051471, 29505567, 14564077, 14564066, 23079138, 9097956, 29460029, 30682568, 31102713) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 02, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	This sequence change creates a premature translational stop signal (p.Arg549*) 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 hypophosphatemia (PMID: 9097956, 24836714, 29460029). ClinVar contains an entry for this variant (Variation ID: 279870). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	39
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.72	D
M_CAP	Uncertain	0.25	D
Vest4		0.98
GERP RS		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.48
dbscSNV1_RF	Pathogenic	0.76
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

Other links and lift over

dbSNP: rs886041224; hg19: chrX-22208619;