chrX-22094009-G-A

Variant names:

• chrX-22094009-G-A
• rs267606946
• NM_000444.6:c.759G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_000444.6(PHEX):​c.759G>A​(p.Met253Ile) variant causes a missense change. 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PHEX NM_000444.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.89
• Publications: 5 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]

PHEX Gene-Disease associations (from GenCC):

• X-linked dominant hypophosphatemic rickets

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000444.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 135 curated pathogenic missense variants (we use a threshold of 10). The gene has 25 curated benign missense variants. Gene score misZ: 1.7091 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked dominant hypophosphatemic rickets.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888
• PP5: Variant X-22094009-G-A is Pathogenic according to our data. Variant chrX-22094009-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 242724.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHEX	NM_000444.6	c.759G>A	p.Met253Ile	missense_variant	Exon 7 of 22	ENST00000379374.5	NP_000435.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHEX	ENST00000379374.5	c.759G>A	p.Met253Ile	missense_variant	Exon 7 of 22	1	NM_000444.6	ENSP00000368682.4
PHEX	ENST00000684143.1	c.756G>A	p.Met252Ile	missense_variant	Exon 7 of 11			ENSP00000508264.1
PHEX	ENST00000475778.2	n.1185G>A		non_coding_transcript_exon_variant	Exon 7 of 9	5
PHEX	ENST00000684745.1	n.433G>A		non_coding_transcript_exon_variant	Exon 5 of 20

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000269 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jan 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 253 of the PHEX protein (p.Met253Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked hypophosphatemic rickets (PMID: 11502829; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 242724). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PHEX protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.034	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		6.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.12	T
Polyphen		0.99	D
Vest4		0.75
MutPred		0.70		Loss of ubiquitination at K251 (P = 0.069);
MVP		0.96
MPC		1.2
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.93
gMVP		0.92
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

dbSNP: rs267606946; hg19: chrX-22112127;