X-22221681-GA-GAA

Position:

• chrX-22221681-GA-GAA

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.1843dupA​(p.Thr615fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PHEX NM_000444.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.40

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-22221681-G-GA is Pathogenic according to our data. Variant chrX-22221681-G-GA is described in ClinVar as [Pathogenic]. Clinvar id is 280079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHEX	NM_000444.6	c.1843dupA	p.Thr615fs	frameshift_variant	18/22	ENST00000379374.5	NP_000435.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHEX	ENST00000379374.5	c.1843dupA	p.Thr615fs	frameshift_variant	18/22	1	NM_000444.6	ENSP00000368682.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 20, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2016	The c.1843dupA pathogenic variant in the PHEX gene has been reported previously in associationwith hypophosphatemic rickets (Gaucher et al., 2009). The duplication causes a frameshift startingwith codon Threonine 615, changes this amino acid to an Asparagine residue and creates a prematureStop codon at position 6 of the new reading frame, denoted p.Thr615AsnfsX6. This pathogenicvariant is predicted to cause loss of normal protein function either through protein truncation ornonsense-mediated mRNA decay. In addition, the c.1843dupA variant was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 07, 2023	This sequence change creates a premature translational stop signal (p.Thr615Asnfs*6) 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: 19219621, 34141703). This variant is also known as c.1843insA (p.Thr615AsnfsX5). ClinVar contains an entry for this variant (Variation ID: 280079). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs886041366; hg19: chrX-22239798;