dbSNP rs147859619: PHEX:p.Glu4Lys (chrX-22033015-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

The NM_000444.6(PHEX):c.10G>A(p.Glu4Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E4Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 22)

Failed GnomAD Quality Control

Consequence

PHEX
NM_000444.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.17

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

X-linked dominant hypophosphatemic rickets
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Orphanet

PHEX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 135 curated pathogenic missense variants (we use a threshold of 10). The gene has 25 curated benign missense variants. Gene score misZ: 1.7091 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked dominant hypophosphatemic rickets.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHEX	NM_000444.6 link	c.10G>A	p.Glu4Lys	missense_variant	Exon 1 of 22	ENST00000379374.5	NP_000435.3	P78562B4DWG8
PHEX	NM_001282754.2 link	c.10G>A	p.Glu4Lys	missense_variant	Exon 1 of 21		NP_001269683.1	P78562B4DNS0B4DWG8
PHEX	XM_047442159.1 link	c.10G>A	p.Glu4Lys	missense_variant	Exon 1 of 13		XP_047298115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PHEX	ENST00000379374.5 link	c.10G>A	p.Glu4Lys	missense_variant	Exon 1 of 22	1	NM_000444.6	ENSP00000368682.4	P78562
PHEX	ENST00000684143.1 link	c.10G>A	p.Glu4Lys	missense_variant	Exon 1 of 11			ENSP00000508264.1	A0A804HLA0
PHEX	ENST00000475778.2 link	n.436G>A		non_coding_transcript_exon_variant	Exon 1 of 9	5
PHEX	ENST00000683214.1 link	n.436G>A		non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

110503

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

110503

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32715

African (AFR)

AF:

0.00

AC:

AN:

30293

American (AMR)

AF:

0.00

AC:

AN:

10269

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2632

East Asian (EAS)

AF:

0.00

AC:

AN:

3540

South Asian (SAS)

AF:

0.00

AC:

AN:

2518

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5930

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52908

Other (OTH)

AF:

0.00

AC:

AN:

1491

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.57

MetaRNN

Uncertain

0.49

MetaSVM

Uncertain

0.086

MutationAssessor

Benign

1.8

PhyloP100

6.2

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.070

REVEL

Uncertain

0.39

Sift

Benign

0.049

Sift4G

Uncertain

0.050

Polyphen

0.96

Vest4

0.36

MutPred

0.17

Gain of ubiquitination at E4 (P = 0.006);

MVP

0.94

MPC

1.2

ClinPred

0.78

GERP RS

5.8

PromoterAI

-0.020

Neutral

(source)

Varity_R

0.28

gMVP

0.84

Mutation Taster

=68/32

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over