rs1064793228

Variant names:

• chrX-22168390-G-A
• rs1064793228
• NM_000444.6:c.1482+1G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-22168390-G-A
• chrX-22168390-G-C
• chrX-22168390-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000444.6(PHEX):​c.1482+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PHEX NM_000444.6 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.53
• 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: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.034666665 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-22168390-G-A is Pathogenic according to our data. Variant chrX-22168390-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 418407.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.1482+1G>A		splice_donor intron	N/A	NP_000435.3
	PHEX	NM_001282754.2		c.1482+1G>A		splice_donor intron	N/A	NP_001269683.1
	PHEX-AS1	NR_046639.1		n.1267+1404C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	ENST00000379374.5	TSL:1 MANE Select	c.1482+1G>A		splice_donor intron	N/A	ENSP00000368682.4	P78562
	PHEX	ENST00000684356.1		c.36+1G>A		splice_donor intron	N/A	ENSP00000507619.1	A0A804HJR7
	PHEX	ENST00000682888.1		c.36+1G>A		splice_donor intron	N/A	ENSP00000508003.1	A0A804HKN7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1027335 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 305803

African (AFR) AF: 0.00 AC: 0 AN: 25118

American (AMR) AF: 0.00 AC: 0 AN: 35093

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18924

East Asian (EAS) AF: 0.00 AC: 0 AN: 29880

South Asian (SAS) AF: 0.00 AC: 0 AN: 52546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40473

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3836

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 777738

Other (OTH) AF: 0.00 AC: 0 AN: 43727

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	-	-	Familial X-linked hypophosphatemic vitamin D refractory rickets (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	29
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.5
GERP RS		4.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: -1

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

Other links and lift over

dbSNP: rs1064793228; hg19: chrX-22186507;