Variant X-22033007-T-C 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 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

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.90

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 3 pathogenic variants. Next in-frame start position is after 98 codons. Genomic position: 22047154. Lost 0.130 part of the original CDS.

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 rank	MANE	Protein	UniProt
PHEX	NM_000444.6 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 22	ENST00000379374.5	NP_000435.3	P78562B4DWG8
PHEX	NM_001282754.2 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 21		NP_001269683.1	P78562B4DNS0B4DWG8
PHEX	XM_047442159.1 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 13		XP_047298115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PHEX	ENST00000379374.5 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 22	1	NM_000444.6	ENSP00000368682.4	P78562
PHEX	ENST00000684143.1 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 11			ENSP00000508264.1	A0A804HLA0
PHEX	ENST00000475778.2 link	n.428T>C		non_coding_transcript_exon_variant	Exon 1 of 9	5
PHEX	ENST00000683214.1 link	n.428T>C		non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1084723

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

May 23, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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. 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

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.41

PROVEAN

Benign

0.26

REVEL

Uncertain

0.56

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Polyphen

0.72

Vest4

0.89

MutPred

0.56

Gain of glycosylation at M1 (P = 0.0095);

MVP

0.96

ClinPred

0.97

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over