rs886041226

Variant names:

• chrX-22245366-C-T
• rs886041226
• NM_000444.6:c.2104C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000444.6(PHEX):​c.2104C>T​(p.Arg702*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: PHEX NM_000444.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.910
• Publications: 7 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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 66 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-22245366-C-T is Pathogenic according to our data. Variant chrX-22245366-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 279872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	NM_000444.6	MANE Select	c.2104C>T	p.Arg702*	stop_gained	Exon 21 of 22	NP_000435.3
	PHEX	NM_001282754.2		c.2071-2485C>T		intron	N/A	NP_001269683.1
	PTCHD1-AS	NR_073010.2		n.850+8573G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	ENST00000379374.5	TSL:1 MANE Select	c.2104C>T	p.Arg702*	stop_gained	Exon 21 of 22	ENSP00000368682.4
	PHEX	ENST00000684356.1		c.658C>T	p.Arg220*	stop_gained	Exon 11 of 12	ENSP00000507619.1
	PHEX	ENST00000683162.1		n.658C>T		non_coding_transcript_exon	Exon 10 of 12	ENSP00000508059.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Familial X-linked hypophosphatemic vitamin D refractory rickets (3)
3	-	-	not provided (3)
1	-	-	PHEX-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		0.91
Vest4		0.85
GERP RS		-0.25
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs886041226; hg19: chrX-22263483;