chrX-22168318-GCTGTTT-G

Position:

• chrX-22168318-GCTGTTT-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM4 PP3 PP5_Moderate

The NM_000444.6(PHEX):​c.1412_1417del​(p.Ala471_Leu473delinsVal) variant causes a inframe deletion 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 (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: PHEX NM_000444.6 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.65

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-AS1 (HGNC:40445): (PHEX antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000444.6.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant X-22168318-GCTGTTT-G is Pathogenic according to our data. Variant chrX-22168318-GCTGTTT-G is described in ClinVar as [Pathogenic]. Clinvar id is 1035780.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHEX	NM_000444.6	c.1412_1417del	p.Ala471_Leu473delinsVal	inframe_deletion	13/22	ENST00000379374.5	NP_000435.3
PHEX-AS1	NR_046639.1	n.1267+1470_1267+1475del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHEX	ENST00000379374.5	c.1412_1417del	p.Ala471_Leu473delinsVal	inframe_deletion	13/22	1	NM_000444.6	ENSP00000368682	P1
PHEX-AS1	ENST00000424650.1	n.1267+1470_1267+1475del		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 22

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

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 14, 2023

This variant, c.1412_1417del, is a complex sequence change that results in the deletion of 3 and insertion of 1 amino acid(s) in the PHEX protein (p.Ala471_Leu473delinsVal). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with hypophosphatemic rickets (Invitae). ClinVar contains an entry for this variant (Variation ID: 1035780). This variant disrupts a region of the PHEX protein in which other variant(s) (p.Val472Asp) have been determined to be pathogenic (PMID: 34141703; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1933405005; hg19: chrX-22186435;