X-22033007-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_000444.6(PHEX):c.2T>C(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PHEX NM_000444.6 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.90

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000444.6 (PHEX) was described as [Pathogenic] in ClinVar as 942742
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-22033007-T-C is Pathogenic according to our data. Variant chrX-22033007-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1073924.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-22033007-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHEX	NM_000444.6	c.2T>C	p.Met1?	start_lost	1/22	ENST00000379374.5
PHEX	NM_001282754.2	c.2T>C	p.Met1?	start_lost	1/21
PHEX	XM_047442159.1	c.2T>C	p.Met1?	start_lost	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHEX	ENST00000379374.5	c.2T>C	p.Met1?	start_lost	1/22	1	NM_000444.6	P1
PHEX	ENST00000684143.1	c.2T>C	p.Met1?	start_lost	1/11
PHEX	ENST00000475778.2	n.428T>C		non_coding_transcript_exon_variant	1/9	5
PHEX	ENST00000683214.1	n.428T>C		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1084723 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 351233

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 23, 2020

For these reasons, this variant has been classified as Pathogenic. Disruption of the initiator codon has been observed in individuals affected with X-linked hypophosphatemia (PMID: 30682568, Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the PHEX mRNA. The next in-frame methionine is located at codon 98. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.41	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	0.26	N
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.72	P
Vest4		0.89
MutPred		0.56		Gain of glycosylation at M1 (P = 0.0095);
MVP		0.96
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.69
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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-22051125;