rs886042234

Variant names:

• chrX-22178374-AGAGT-A
• rs886042234
• NM_000444.6:c.1586+3_1586+6delGAGT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The ENST00000379374.5(PHEX):​c.1585_1586+2delGAGT​(p.Glu529GlyfsTer40) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PHEX ENST00000379374.5 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.83
• 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 11 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-22178374-AGAGT-A is Pathogenic according to our data. Variant chrX-22178374-AGAGT-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 281773.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000379374.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	NM_000444.6	MANE Select	c.1586+3_1586+6delGAGT		splice_region intron	N/A	NP_000435.3
	PHEX	NM_001282754.2		c.1586+3_1586+6delGAGT		splice_region intron	N/A	NP_001269683.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	ENST00000379374.5	TSL:1 MANE Select	c.1585_1586+2delGAGT	p.Glu529GlyfsTer40	frameshift splice_donor splice_region intron	Exon 14 of 22	ENSP00000368682.4	P78562
	PHEX	ENST00000684356.1		c.139_140+2delGAGT	p.Glu47GlyfsTer40	frameshift splice_donor splice_region intron	Exon 4 of 12	ENSP00000507619.1	A0A804HJR7
	PHEX	ENST00000682888.1		c.139_140+2delGAGT	p.Glu47GlyfsTer40	frameshift splice_donor splice_region intron	Exon 3 of 8	ENSP00000508003.1	A0A804HKN7

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

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Familial X-linked hypophosphatemic vitamin D refractory rickets (2)
1	1	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: 2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs886042234;

hg19: chrX-22196491;