rs1240767654

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_000444.6(PHEX):​c.1965+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 Pathogenic (★★).

Frequency

Genomes: not found (cov: 22)

Consequence

PHEX
NM_000444.6 splice_donor, intron

Scores

3
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 8.04
Variant links:
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))

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.028888889 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-22226509-G-A is Pathogenic according to our data. Variant chrX-22226509-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 438485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-22226509-G-A is described in Lovd as [Pathogenic]. Variant chrX-22226509-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PHEXNM_000444.6 linkc.1965+1G>A splice_donor_variant, intron_variant ENST00000379374.5 NP_000435.3 P78562B4DWG8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PHEXENST00000379374.5 linkc.1965+1G>A splice_donor_variant, intron_variant 1 NM_000444.6 ENSP00000368682.4 P78562

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
22
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial X-linked hypophosphatemic vitamin D refractory rickets Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics Munich, Klinikum Rechts Der Isar, TU MünchenJun 12, 2017- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 11, 2022ClinVar contains an entry for this variant (Variation ID: 438485). Disruption of this splice site has been observed in individual(s) with hypophosphatemic rickets (PMID: 9097956, 18162710, 19219621, 29460029, 30682568). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 19 of the PHEX gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PHEX are known to be pathogenic (PMID: 9097956, 9106524, 19219621). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.74
D
BayesDel_noAF
Pathogenic
0.37
CADD
Pathogenic
27
DANN
Uncertain
1.0
FATHMM_MKL
Pathogenic
0.99
D
GERP RS
5.9

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1240767654; hg19: chrX-22244626; API