X-22190447-G-A

Variant names:

• chrX-22190447-G-A
• rs1556091855
• NM_000444.6:c.1590G>A

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.1590G>A​(p.Trp530*) variant causes a stop gained change. 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PHEX NM_000444.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.55
• 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 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-22190447-G-A is Pathogenic according to our data. Variant chrX-22190447-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1459874.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.1590G>A	p.Trp530*	stop_gained	Exon 15 of 22	NP_000435.3
	PHEX	NM_001282754.2		c.1590G>A	p.Trp530*	stop_gained	Exon 15 of 21	NP_001269683.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	ENST00000379374.5	TSL:1 MANE Select	c.1590G>A	p.Trp530*	stop_gained	Exon 15 of 22	ENSP00000368682.4
	PHEX	ENST00000684356.1		c.144G>A	p.Trp48*	stop_gained	Exon 5 of 12	ENSP00000507619.1
	PHEX	ENST00000682888.1		c.144G>A	p.Trp48*	stop_gained	Exon 4 of 8	ENSP00000508003.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1079089 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 346675

African (AFR) AF: 0.00 AC: 0 AN: 26058

American (AMR) AF: 0.00 AC: 0 AN: 35191

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19269

East Asian (EAS) AF: 0.00 AC: 0 AN: 30123

South Asian (SAS) AF: 0.00 AC: 0 AN: 53739

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4086

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 824620

Other (OTH) AF: 0.00 AC: 0 AN: 45481

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jan 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 1459874). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with X-linked hypophosphatemia (PMID: 9768674). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp530*) in the PHEX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PHEX are known to be pathogenic (PMID: 9097956, 9106524, 19219621).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	41
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		6.6
Vest4		0.94
GERP RS		5.5
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs1556091855; hg19: chrX-22208564;