X-22033030-GTGGAGAC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000444.6(PHEX):c.30_36del(p.Thr11ArgfsTer19) variant causes a frameshift 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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.47

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 Pathogenic. Variant got 12 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 427 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-22033030-GTGGAGAC-G is Pathogenic according to our data. Variant chrX-22033030-GTGGAGAC-G is described in ClinVar as [Pathogenic]. Clinvar id is 937183.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-22033030-GTGGAGAC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHEX	NM_000444.6	c.30_36del	p.Thr11ArgfsTer19	frameshift_variant	1/22	ENST00000379374.5
PHEX	NM_001282754.2	c.30_36del	p.Thr11ArgfsTer19	frameshift_variant	1/21
PHEX	XM_047442159.1	c.30_36del	p.Thr11ArgfsTer19	frameshift_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHEX	ENST00000379374.5	c.30_36del	p.Thr11ArgfsTer19	frameshift_variant	1/22	1	NM_000444.6	P1
PHEX	ENST00000684143.1	c.30_36del	p.Thr11ArgfsTer19	frameshift_variant	1/11
PHEX	ENST00000475778.2	n.456_462del		non_coding_transcript_exon_variant	1/9	5
PHEX	ENST00000683214.1	n.456_462del		non_coding_transcript_exon_variant	1/2

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

Invitae

Sep 24, 2019

This sequence change creates a premature translational stop signal (p.Thr11Argfs*19) in the PHEX gene. It is expected to result in an absent or disrupted protein product. 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). -

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: rs1926867732; hg19: chrX-22051148;