chrX-22168389-TG-T

Position:

• chrX-22168389-TG-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_000444.6(PHEX):​c.1482+1del variant causes a splice donor 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PHEX NM_000444.6 splice_donor
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.53

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-AS1 (HGNC:40445): (PHEX antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.034222223 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-22168389-TG-T is Pathogenic according to our data. Variant chrX-22168389-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2585572.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHEX	NM_000444.6	c.1482+1del		splice_donor_variant		ENST00000379374.5	NP_000435.3
PHEX-AS1	NR_046639.1	n.1267+1404del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHEX	ENST00000379374.5	c.1482+1del		splice_donor_variant		1	NM_000444.6	ENSP00000368682	P1
PHEX-AS1	ENST00000424650.1	n.1267+1404del		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial X-linked hypophosphatemic vitamin D refractory rickets Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

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Consanguinity- Absent Clinical indication- Bowing of leg, hypophosphotemic rickets, H/o operated for deformity b/l medial distal femoral and proximal tibial plate application for hemiepiphysiodesis. Family history- Mother- short stature. Mother's uncle- History of renal stone. Clinical diagnosis- Hypophosphatemic rickets. -

Computational scores

Source: dbNSFP v4.3

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: 0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-22186506;