rs1064793956

Variant names:

• chrX-22090443-ACT-A
• rs1064793956
• NM_000444.6:c.682_683delTC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000444.6(PHEX):​c.682_683delTC​(p.Ser228ProfsTer9) variant causes a frameshift change. 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: 6.09
• Publications: 0 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: Pathogenic. The variant received 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-22090443-ACT-A is Pathogenic according to our data. Variant chrX-22090443-ACT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 419563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHEX	NM_000444.6	c.682_683delTC	p.Ser228ProfsTer9	frameshift_variant	Exon 6 of 22	ENST00000379374.5	NP_000435.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHEX	ENST00000379374.5	c.682_683delTC	p.Ser228ProfsTer9	frameshift_variant	Exon 6 of 22	1	NM_000444.6	ENSP00000368682.4
PHEX	ENST00000684143.1	c.679_680delTC	p.Ser227ProfsTer9	frameshift_variant	Exon 6 of 11			ENSP00000508264.1
PHEX	ENST00000475778.2	n.1108_1109delTC		non_coding_transcript_exon_variant	Exon 6 of 9	5
PHEX	ENST00000684745.1	n.356_357delTC		non_coding_transcript_exon_variant	Exon 4 of 20

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial X-linked hypophosphatemic vitamin D refractory rickets Pathogenic:2

Oct 28, 2013

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Aug 12, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.682_683delTC deletion in the PHEX gene has been reported previously in association with X-Linked hypophosphatemic rickets (Francis et al., 1995). The deletion causes a frameshift starting with codon Serine 228, changes this amino acid to a Proline residue and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Ser228ProfsX9. This deletion is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, we interpret the c.682_683delTC variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1064793956; hg19: chrX-22108561;