NM_000444.6:c.1479dupA

Variant names:

• chrX-22168383-C-CA
• rs2147118833
• NM_000444.6:c.1479dupA

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.1479dupA​(p.Ala494SerfsTer24) variant causes a frameshift, splice region change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PHEX NM_000444.6 frameshift, splice_region
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.09
• 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))

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

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-22168383-C-CA is Pathogenic according to our data. Variant chrX-22168383-C-CA is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1687473.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	NM_000444.6	MANE Select	c.1479dupA	p.Ala494SerfsTer24	frameshift splice_region	Exon 13 of 22	NP_000435.3
	PHEX	NM_001282754.2		c.1479dupA	p.Ala494SerfsTer24	frameshift splice_region	Exon 13 of 21	NP_001269683.1
	PHEX-AS1	NR_046639.1		n.1267+1410dupT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	ENST00000379374.5	TSL:1 MANE Select	c.1479dupA	p.Ala494SerfsTer24	frameshift splice_region	Exon 13 of 22	ENSP00000368682.4	P78562
	PHEX	ENST00000684356.1		c.33dupA	p.Ala12SerfsTer24	frameshift splice_region	Exon 3 of 12	ENSP00000507619.1	A0A804HJR7
	PHEX	ENST00000682888.1		c.33dupA	p.Ala12SerfsTer24	frameshift splice_region	Exon 2 of 8	ENSP00000508003.1	A0A804HKN7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Familial X-linked hypophosphatemic vitamin D refractory rickets (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1

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: rs2147118833; hg19: chrX-22186500;