NM_000444.6:c.1445_1482+235del

Variant names:

• chrX-22168350-TATAATGAATGATACTCATGTTAATGAAGACCTCAAAGCTGTAAGTGCTAAATTTACTGTACTTTTTTTTTTCTGGCAAGTTTTACTGGCCTTGTGCCTTTCAACTAACCCAAGTCCTAGCAATTAAAACTGGTGATGCCAGAAAACACCAACTTTTGATTAATTCCTTGGCTAGATATGAGCCTGAATATGCCAGGCAGATCACAAGATTTAGGGCAGATTCAAAATAAAGAAGTGTCAGAAACGATGCGTAGCTGAGTGGGTACCAAAAAAC-T
• NM_000444.6:c.1445_1482+235del

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000444.6(PHEX):​c.1445_1482+235del​(p.Ile482AlafsTer178) variant causes a frameshift, splice donor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PHEX NM_000444.6 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.09

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-AS1 (HGNC:):

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

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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 rank	MANE	Protein	UniProt
PHEX	NM_000444.6	c.1445_1482+235del	p.Ile482AlafsTer178	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 13 of 22	ENST00000379374.5	NP_000435.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHEX	ENST00000379374.5	c.1444_1482+234del	p.Ile482_Ala494del	splice_donor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 13 of 22	1	NM_000444.6	ENSP00000368682.4

Frequencies

GnomAD3 genomes Cov.: 22

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

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jan 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with hypophosphatemia (Invitae). 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

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-22186467;