NM_000444.6:c.30_36delGACTGGA

Variant names:

• chrX-22033030-GTGGAGAC-G
• rs1926867732
• NM_000444.6:c.30_36delGACTGGA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000444.6(PHEX):​c.30_36delGACTGGA​(p.Thr11ArgfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: PHEX NM_000444.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.47

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 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 16 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-22033030-GTGGAGAC-G is Pathogenic according to our data. Variant chrX-22033030-GTGGAGAC-G is described in ClinVar as [Pathogenic]. Clinvar id is 937183.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-22033030-GTGGAGAC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHEX	NM_000444.6	c.30_36delGACTGGA	p.Thr11ArgfsTer19	frameshift_variant	Exon 1 of 22	ENST00000379374.5	NP_000435.3
PHEX	NM_001282754.2	c.30_36delGACTGGA	p.Thr11ArgfsTer19	frameshift_variant	Exon 1 of 21		NP_001269683.1
PHEX	XM_047442159.1	c.30_36delGACTGGA	p.Thr11ArgfsTer19	frameshift_variant	Exon 1 of 13		XP_047298115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHEX	ENST00000379374.5	c.30_36delGACTGGA	p.Thr11ArgfsTer19	frameshift_variant	Exon 1 of 22	1	NM_000444.6	ENSP00000368682.4
PHEX	ENST00000684143.1	c.30_36delGACTGGA	p.Thr11ArgfsTer19	frameshift_variant	Exon 1 of 11			ENSP00000508264.1
PHEX	ENST00000475778.2	n.456_462delGACTGGA		non_coding_transcript_exon_variant	Exon 1 of 9	5
PHEX	ENST00000683214.1	n.456_462delGACTGGA		non_coding_transcript_exon_variant	Exon 1 of 2

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: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Sep 24, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Thr11Argfs*19) in the PHEX gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PHEX-related conditions. Loss-of-function variants in PHEX are known to be pathogenic (PMID: 9097956, 9106524, 19219621). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1926867732; hg19: chrX-22051148;