Variant chrX-22168350-TATAATGAATGATACTCATGTTAATGAAGACCTCAAAGCTGTAAGTGCTAAATTTACTGTACTTTTTTTTTTCTGGCAAGTTTTACTGGCCTTGTGCCTTTCAACTAACCCAAGTCCTAGCAATTAAAACTGGTGATGCCAGAAAACACCAACTTTTGATTAATTCCTTGGCTAGATATGAGCCTGAATATGCCAGGCAGATCACAAGATTTAGGGCAGATTCAAAATAAAGAAGTGTCAGAAACGATGCGTAGCTGAGTGGGTACCAAAAAAC-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The ENST00000379374.5(PHEX):c.1445_1482+235del variant causes a splice donor, splice donor 5th base, coding sequence, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 22)

Consequence

PHEX
ENST00000379374.5 splice_donor, splice_donor_5th_base, coding_sequence, intron

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.09

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]

PHEX links:

PHEX-AS1 (HGNC:40445): (PHEX antisense RNA 1)

PHEX-AS1 links:

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ACMG classification

Classification made for transcript

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 0.034222223 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-22168350-TATAATGAATGATACTCATGTTAATGAAGACCTCAAAGCTGTAAGTGCTAAATTTACTGTACTTTTTTTTTTCTGGCAAGTTTTACTGGCCTTGTGCCTTTCAACTAACCCAAGTCCTAGCAATTAAAACTGGTGATGCCAGAAAACACCAACTTTTGATTAATTCCTTGGCTAGATATGAGCCTGAATATGCCAGGCAGATCACAAGATTTAGGGCAGATTCAAAATAAAGAAGTGTCAGAAACGATGCGTAGCTGAGTGGGTACCAAAAAAC-T is Pathogenic according to our data. Variant chrX-22168350-TATAATGAATGATACTCATGTTAATGAAGACCTCAAAGCTGTAAGTGCTAAATTTACTGTACTTTTTTTTTTCTGGCAAGTTTTACTGGCCTTGTGCCTTTCAACTAACCCAAGTCCTAGCAATTAAAACTGGTGATGCCAGAAAACACCAACTTTTGATTAATTCCTTGGCTAGATATGAGCCTGAATATGCCAGGCAGATCACAAGATTTAGGGCAGATTCAAAATAAAGAAGTGTCAGAAACGATGCGTAGCTGAGTGGGTACCAAAAAAC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1914055.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHEX	NM_000444.6 linkuse as main transcript	c.1445_1482+235del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	13/22	ENST00000379374.5	NP_000435.3
PHEX-AS1	NR_046639.1 linkuse as main transcript	n.1267+1171_1267+1443del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHEX	ENST00000379374.5 linkuse as main transcript	c.1445_1482+235del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	13/22	1	NM_000444.6	ENSP00000368682	P1
PHEX-AS1	ENST00000424650.1 linkuse as main transcript	n.1267+1171_1267+1443del		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

Cov.:

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

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2022

This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been observed in individual(s) with hypophosphatemia (Invitae). This variant results in the deletion of part of exon 13 (c.1445_1482+235del) 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

No publications associated with this variant yet.