X-22033063-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.58C>T(p.Arg20Ter) 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:5
• Conservation: PhyloP100: 1.74

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 425 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-22033063-C-T is Pathogenic according to our data. Variant chrX-22033063-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 379502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-22033063-C-T is described in Lovd as [Pathogenic]. Variant chrX-22033063-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHEX	NM_000444.6	c.58C>T	p.Arg20Ter	stop_gained	1/22	ENST00000379374.5
PHEX	NM_001282754.2	c.58C>T	p.Arg20Ter	stop_gained	1/21
PHEX	XM_047442159.1	c.58C>T	p.Arg20Ter	stop_gained	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHEX	ENST00000379374.5	c.58C>T	p.Arg20Ter	stop_gained	1/22	1	NM_000444.6	P1
PHEX	ENST00000684143.1	c.58C>T	p.Arg20Ter	stop_gained	1/11
PHEX	ENST00000475778.2	n.484C>T		non_coding_transcript_exon_variant	1/9	5
PHEX	ENST00000683214.1	n.484C>T		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	Jan 13, 2022	- -
Pathogenic, no assertion criteria provided	research	Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	May 31, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Oct 28, 2013	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 22, 2023	This sequence change creates a premature translational stop signal (p.Arg20*) 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 X-linked hypophosphatemic rickets (PMID: 9097956, 9199930). ClinVar contains an entry for this variant (Variation ID: 379502). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2016	The R20X nonsense variant in the PHEX gene has been frequently reported in association withX-Linked Hypophosphatemic Rickets (Rowe et al., 1997; Francis et al., 1997; Cho et al., 2005). TheR20X variant was not observed in approximately 6,500 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant inthese populations. This pathogenic variant is predicted to cause loss of normal protein function eitherthrough protein truncation or nonsense-mediated mRNA decay. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Pathogenic	34
Dann	Uncertain	1.0
FATHMM_MKL	Benign	0.30	N
MutationTaster	Benign	1.0	A;A
Vest4		0.79
GERP RS		4.0

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

Other links and lift over

dbSNP: rs770573978; hg19: chrX-22051181; COSMIC: COSV65076754;