rs770573978

Variant names:

• chrX-22033063-C-T
• rs770573978
• NM_000444.6:c.58C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-22033063-C-T
• chrX-22033063-C-A
• chrX-22033063-C-G

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.58C>T​(p.Arg20*) 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:5
• Conservation: PhyloP100: 1.74
• Publications: 8 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]

PHEX Gene-Disease associations (from GenCC):

• X-linked dominant hypophosphatemic rickets

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Orphanet, ClinGen

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 located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 640 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-22033063-C-T is Pathogenic according to our data. Variant chrX-22033063-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 379502.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.58C>T	p.Arg20*	stop_gained	Exon 1 of 22	NP_000435.3
	PHEX	NM_001282754.2		c.58C>T	p.Arg20*	stop_gained	Exon 1 of 21	NP_001269683.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	ENST00000379374.5	TSL:1 MANE Select	c.58C>T	p.Arg20*	stop_gained	Exon 1 of 22	ENSP00000368682.4	P78562
	PHEX	ENST00000684143.1		c.58C>T	p.Arg20*	stop_gained	Exon 1 of 11	ENSP00000508264.1	A0A804HLA0
	PHEX	ENST00000475778.2	TSL:5	n.484C>T		non_coding_transcript_exon	Exon 1 of 9

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Familial X-linked hypophosphatemic vitamin D refractory rickets (3)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	34
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.30	N
PhyloP100		1.7
Vest4		0.79
GERP RS		4.0
PromoterAI		-0.0093	Neutral
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: rs770573978; hg19: chrX-22051181; COSMIC: COSV65076754;