rs886041225

Variant names:

• chrX-22190503-G-A
• rs886041225
• NM_000444.6:c.1645+1G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-22190503-G-A
• chrX-22190503-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000444.6(PHEX):​c.1645+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000957 in 1,045,332 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.6e-7 (0 hom. 0 hem.)
• Consequence: PHEX NM_000444.6 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.55
• Publications: 7 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 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.5, offset of 26, new splice context is: ttgGTaacc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-22190503-G-A is Pathogenic according to our data. Variant chrX-22190503-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 279871.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.1645+1G>A		splice_donor intron	N/A	NP_000435.3
	PHEX	NM_001282754.2		c.1645+1G>A		splice_donor intron	N/A	NP_001269683.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	ENST00000379374.5	TSL:1 MANE Select	c.1645+1G>A		splice_donor intron	N/A	ENSP00000368682.4	P78562
	PHEX	ENST00000684356.1		c.199+1G>A		splice_donor intron	N/A	ENSP00000507619.1	A0A804HJR7
	PHEX	ENST00000682888.1		c.199+1G>A		splice_donor intron	N/A	ENSP00000508003.1	A0A804HKN7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.57e-7 AC: 1 AN: 1045332 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 317734

African (AFR) AF: 0.00 AC: 0 AN: 25377

American (AMR) AF: 0.00 AC: 0 AN: 35160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19059

East Asian (EAS) AF: 0.00 AC: 0 AN: 29998

South Asian (SAS) AF: 0.00 AC: 0 AN: 52921

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40509

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3999

European-Non Finnish (NFE) AF: 0.00000126 AC: 1 AN: 793901

Other (OTH) AF: 0.00 AC: 0 AN: 44408

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	33
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		6.6
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
Splicevardb		3.0
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: -1

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs886041225;

hg19: chrX-22208620;

COSMIC: COSV65075053;