NM_000444.6:c.1405-2_1415delAGGCGAGAGCTGT

Variant names:

• chrX-22168306-TTGTAGGCGAGAGC-T
• NM_000444.6:c.1405-2_1415delAGGCGAGAGCTGT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_000444.6(PHEX):​c.1405-2_1415delAGGCGAGAGCTGT​(p.Ala469fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A469A) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PHEX NM_000444.6 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.65
• 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 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant X-22168306-TTGTAGGCGAGAGC-T is Pathogenic according to our data. Variant chrX-22168306-TTGTAGGCGAGAGC-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2106299.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.1405-2_1415delAGGCGAGAGCTGT	p.Ala469fs	frameshift splice_acceptor splice_region intron	Exon 13 of 22	NP_000435.3
	PHEX	NM_001282754.2		c.1405-2_1415delAGGCGAGAGCTGT	p.Ala469fs	frameshift splice_acceptor splice_region intron	Exon 13 of 21	NP_001269683.1
	PHEX-AS1	NR_046639.1		n.1267+1475_1267+1487delGCTCTCGCCTACA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	ENST00000379374.5	TSL:1 MANE Select	c.1405-5_1412delTGTAGGCGAGAGC	p.Ala469fs	frameshift splice_acceptor splice_region intron	Exon 13 of 22	ENSP00000368682.4	P78562
	PHEX	ENST00000684356.1		c.-42-5_-35delTGTAGGCGAGAGC		splice_region	Exon 3 of 12	ENSP00000507619.1	A0A804HJR7
	PHEX	ENST00000682888.1		c.-42-5_-35delTGTAGGCGAGAGC		splice_region	Exon 2 of 8	ENSP00000508003.1	A0A804HKN7

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7

Splicing

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

Other links and lift over

hg19: chrX-22186423;