rs886041227

Variant names:

• chrX-22247942-C-T
• rs886041227
• NM_000444.6:c.2239C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000444.6(PHEX):​c.2239C>T​(p.Arg747*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000924 in 1,082,726 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: PHEX NM_000444.6 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 2.06
• Publications: 11 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 14 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 11 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-22247942-C-T is Pathogenic according to our data. Variant chrX-22247942-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 279873.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.2239C>T	p.Arg747*	stop_gained	Exon 22 of 22	NP_000435.3
	PHEX	NM_001282754.2		c.*74C>T		3_prime_UTR	Exon 21 of 21	NP_001269683.1
	PTCHD1-AS	NR_073010.2		n.850+5997G>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.2239C>T	p.Arg747*	stop_gained	Exon 22 of 22	ENSP00000368682.4	P78562
	PHEX	ENST00000684356.1		c.793C>T	p.Arg265*	stop_gained	Exon 12 of 12	ENSP00000507619.1	A0A804HJR7
	PHEX	ENST00000683162.1		n.*177C>T		non_coding_transcript_exon	Exon 12 of 12	ENSP00000508059.1	A0A804HKT0

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.24e-7 AC: 1 AN: 1082726 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 348838

African (AFR) AF: 0.0000382 AC: 1 AN: 26146

American (AMR) AF: 0.00 AC: 0 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19301

East Asian (EAS) AF: 0.00 AC: 0 AN: 30146

South Asian (SAS) AF: 0.00 AC: 0 AN: 53766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4101

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 827974

Other (OTH) AF: 0.00 AC: 0 AN: 45583

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Familial X-linked hypophosphatemic vitamin D refractory rickets (5)
4	-	-	not provided (4)
1	-	-	Autosomal dominant hypophosphatemic rickets (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		2.1
Vest4		0.68
GERP RS		3.9
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs886041227; hg19: chrX-22266059; COSMIC: COSV65073821;