X-22033026-C-ACTGG

Variant names:

• chrX-22033026-C-ACTGG
• rs1926867009
• NM_000444.6:c.21delCinsACTGG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000444.6(PHEX):​c.21delCinsACTGG​(p.Ser7ArgfsTer45) variant causes a frameshift, missense change involving the alteration of a non-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 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.37

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 Likely_pathogenic. Variant got 8 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 16 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-22033026-C-ACTGG is Pathogenic according to our data. Variant chrX-22033026-C-ACTGG is described in ClinVar as [Pathogenic]. Clinvar id is 966338.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.21delCinsACTGG	p.Ser7ArgfsTer45	frameshift_variant, missense_variant	Exon 1 of 22	ENST00000379374.5	NP_000435.3
PHEX	NM_001282754.2	c.21delCinsACTGG	p.Ser7ArgfsTer45	frameshift_variant, missense_variant	Exon 1 of 21		NP_001269683.1
PHEX	XM_047442159.1	c.21delCinsACTGG	p.Ser7ArgfsTer45	frameshift_variant, missense_variant	Exon 1 of 13		XP_047298115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHEX	ENST00000379374.5	c.21delCinsACTGG	p.Ser7ArgfsTer45	frameshift_variant, missense_variant	Exon 1 of 22	1	NM_000444.6	ENSP00000368682.4
PHEX	ENST00000684143.1	c.21delCinsACTGG	p.Ser7ArgfsTer45	frameshift_variant, missense_variant	Exon 1 of 11			ENSP00000508264.1
PHEX	ENST00000475778.2	n.447delCinsACTGG		non_coding_transcript_exon_variant	Exon 1 of 9	5
PHEX	ENST00000683214.1	n.447delCinsACTGG		non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Dec 06, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PHEX are known to be pathogenic (PMID: 9097956, 9106524, 19219621). This variant has not been reported in the literature in individuals with PHEX-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser7Argfs*45) in the PHEX gene. It is expected to result in an absent or disrupted protein product. -

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: rs1926867009; hg19: chrX-22051144;