rs1057518896

Variant names:

• chrX-22247868-G-GTAAC
• rs1057518896
• NM_000444.6:c.2167_2170dupAACT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000444.6(PHEX):​c.2167_2170dupAACT​(p.Phe724fs) variant causes a frameshift, stop gained 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: 23)
• Consequence: PHEX NM_000444.6 frameshift, stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.30
• 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]

PTCHD1-AS (HGNC:37703): (PTCHD1 antisense RNA (head to head))

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 39 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-22247868-G-GTAAC is Pathogenic according to our data. Variant chrX-22247868-G-GTAAC is described in ClinVar as Pathogenic. ClinVar VariationId is 374096.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000444.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	NM_000444.6	MANE Select	c.2167_2170dupAACT	p.Phe724fs	frameshift stop_gained	Exon 22 of 22	NP_000435.3
	PHEX	NM_001282754.2		c.*2_*5dupAACT		3_prime_UTR	Exon 21 of 21	NP_001269683.1
	PTCHD1-AS	NR_073010.2		n.850+6067_850+6070dupGTTA		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	ENST00000379374.5	TSL:1 MANE Select	c.2167_2170dupAACT	p.Phe724fs	frameshift stop_gained	Exon 22 of 22	ENSP00000368682.4
	PHEX	ENST00000684356.1		c.721_724dupAACT	p.Phe242fs	frameshift stop_gained	Exon 12 of 12	ENSP00000507619.1
	PHEX	ENST00000683162.1		n.*105_*108dupAACT		non_coding_transcript_exon	Exon 12 of 12	ENSP00000508059.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Lower limb pain;C1704375:Hypophosphatemic rickets;C5574706:Bowing of the legs (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1057518896; hg19: chrX-22265985;