X-22038538-G-C

Variant names:

• chrX-22038538-G-C
• NM_000444.6:c.187+1G>C

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.187+1G>C 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)
• Consequence: PHEX NM_000444.6 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.56

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]

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 0.030666666 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.7, offset of 41, new splice context is: atgGTacct. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-22038538-G-C is Pathogenic according to our data. Variant chrX-22038538-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1685396.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-22038538-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHEX	NM_000444.6	c.187+1G>C		splice_donor_variant, intron_variant	Intron 2 of 21	ENST00000379374.5	NP_000435.3
PHEX	NM_001282754.2	c.187+1G>C		splice_donor_variant, intron_variant	Intron 2 of 20		NP_001269683.1
PHEX	XM_024452390.2	c.-105+1G>C		splice_donor_variant, intron_variant	Intron 2 of 21		XP_024308158.1
PHEX	XM_047442159.1	c.187+1G>C		splice_donor_variant, intron_variant	Intron 2 of 12		XP_047298115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHEX	ENST00000379374.5	c.187+1G>C		splice_donor_variant, intron_variant	Intron 2 of 21	1	NM_000444.6	ENSP00000368682.4
PHEX	ENST00000684143.1	c.187+1G>C		splice_donor_variant, intron_variant	Intron 2 of 10			ENSP00000508264.1
PHEX	ENST00000475778.2	n.613+1G>C		splice_donor_variant, intron_variant	Intron 2 of 8	5
PHEX	ENST00000683214.1	n.544+5415G>C		intron_variant	Intron 1 of 1

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

May 04, 2022

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-22056656;