Genetic Variant PHEX:p.Glu4Gln (chrX-22033015-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_000444.6(PHEX):c.10G>C(p.Glu4Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000234 in 1,203,671 control chromosomes in the GnomAD database, including 1 homozygotes. There are 105 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., 14 hem., cov: 22)

Exomes 𝑓: 0.00022 ( 1 hom. 91 hem. )

Consequence

PHEX
NM_000444.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

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: Labcorp Genetics (formerly Invitae), Illumina, Orphanet, ClinGen

PHEX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057458878).

BP6

Variant X-22033015-G-C is Benign according to our data. Variant chrX-22033015-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225437.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000362 (40/110555) while in subpopulation EAS AF = 0.00538 (19/3529). AF 95% confidence interval is 0.00352. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 14 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000444.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	NM_000444.6	MANE Select	c.10G>C	p.Glu4Gln	missense	Exon 1 of 22	NP_000435.3
	PHEX	NM_001282754.2		c.10G>C	p.Glu4Gln	missense	Exon 1 of 21	NP_001269683.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PHEX	ENST00000379374.5	TSL:1 MANE Select	c.10G>C	p.Glu4Gln	missense	Exon 1 of 22	ENSP00000368682.4	P78562
PHEX	ENST00000684143.1		c.10G>C	p.Glu4Gln	missense	Exon 1 of 11	ENSP00000508264.1	A0A804HLA0
PHEX	ENST00000475778.2	TSL:5	n.436G>C		non_coding_transcript_exon	Exon 1 of 9

Frequencies

GnomAD3 genomes

AF:

0.000362

AC:

AN:

110503

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000594

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00537

Gnomad SAS

AF:

0.00119

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000731

AC:

134

AN:

183399

AF XY:

0.000634

show subpopulations

Gnomad AFR exome

AF:

0.000304

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00895

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000442

GnomAD4 exome

AF:

0.000221

AC:

242

AN:

1093116

Hom.:

Cov.:

AF XY:

0.000254

AC XY:

AN XY:

358700

show subpopulations

African (AFR)

AF:

0.0000761

AC:

AN:

26293

American (AMR)

AF:

0.00

AC:

AN:

35202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19354

East Asian (EAS)

AF:

0.00643

AC:

194

AN:

30187

South Asian (SAS)

AF:

0.000389

AC:

AN:

54032

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4117

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

837490

Other (OTH)

AF:

0.000523

AC:

AN:

45913

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000362

AC:

AN:

110555

Hom.:

Cov.:

AF XY:

0.000427

AC XY:

AN XY:

32777

show subpopulations

African (AFR)

AF:

0.000593

AC:

AN:

30360

American (AMR)

AF:

0.00

AC:

AN:

10282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2632

East Asian (EAS)

AF:

0.00538

AC:

AN:

3529

South Asian (SAS)

AF:

0.00120

AC:

AN:

2510

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5930

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52901

Other (OTH)

AF:

0.00

AC:

AN:

1510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000340

Hom.:

Bravo

AF:

0.000567

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000733

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial X-linked hypophosphatemic vitamin D refractory rickets (2)

not specified (2)

not provided (1)

PHEX-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.70

M_CAP

Pathogenic

0.55

MetaRNN

Benign

0.0057

MetaSVM

Uncertain

-0.013

MutationAssessor

Benign

1.8

PhyloP100

6.2

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.010

REVEL

Uncertain

0.54

Sift

Benign

0.051

Sift4G

Benign

0.28

Polyphen

0.98

Vest4

0.11

MVP

0.96

MPC

1.1

ClinPred

0.040

GERP RS

5.8

PromoterAI

-0.024

Neutral

(source)

Varity_R

0.20

gMVP

0.74

Mutation Taster

=77/23

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over