Genetic Variant PHEX:p.Glu490Asp (chrX-22168377-A-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP2BP4BP6_ModerateBS2

The NM_000444.6(PHEX):c.1470A>T(p.Glu490Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000231 in 1,171,362 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000014 ( 0 hom. 6 hem. )

Consequence

PHEX
NM_000444.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.23

Publications

1 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 links:

PTCHD1-AS (HGNC:37703): (PTCHD1 antisense RNA (head to head))

PTCHD1-AS links:

PHEX-AS1 (HGNC:40445): (PHEX antisense RNA 1)

PHEX-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 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=0.27847445).

BP6

Variant X-22168377-A-T is Benign according to our data. Variant chrX-22168377-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1158266.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 6 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PHEX	NM_000444.6	MANE Select	c.1470A>T	p.Glu490Asp	missense	Exon 13 of 22	NP_000435.3
PHEX	NM_001282754.2		c.1470A>T	p.Glu490Asp	missense	Exon 13 of 21	NP_001269683.1
PHEX-AS1	NR_046639.1		n.1267+1417T>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PHEX	ENST00000379374.5	TSL:1 MANE Select	c.1470A>T	p.Glu490Asp	missense	Exon 13 of 22	ENSP00000368682.4	P78562
PHEX	ENST00000684356.1		c.24A>T	p.Glu8Asp	missense	Exon 3 of 12	ENSP00000507619.1	A0A804HJR7
PHEX	ENST00000682888.1		c.24A>T	p.Glu8Asp	missense	Exon 2 of 8	ENSP00000508003.1	A0A804HKN7

Frequencies

GnomAD3 genomes

AF:

0.000107

AC:

AN:

112111

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000356

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000948

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

GnomAD2 exomes

AF:

0.0000273

AC:

AN:

183193

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.000304

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000142

AC:

AN:

1059251

Hom.:

Cov.:

AF XY:

0.0000182

AC XY:

AN XY:

328875

show subpopulations

African (AFR)

AF:

0.000428

AC:

AN:

25710

American (AMR)

AF:

0.0000285

AC:

AN:

35142

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19135

East Asian (EAS)

AF:

0.00

AC:

AN:

30022

South Asian (SAS)

AF:

0.00

AC:

AN:

53246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40498

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3956

European-Non Finnish (NFE)

AF:

0.00000124

AC:

AN:

806788

Other (OTH)

AF:

0.0000447

AC:

AN:

44754

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.000107

AC:

AN:

112111

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34283

show subpopulations

African (AFR)

AF:

0.000356

AC:

AN:

30861

American (AMR)

AF:

0.0000948

AC:

AN:

10546

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3593

South Asian (SAS)

AF:

0.00

AC:

AN:

2719

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6044

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53275

Other (OTH)

AF:

0.00

AC:

AN:

1505

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.076

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.71

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.28

MetaSVM

Uncertain

0.11

MutationAssessor

Uncertain

2.3

PhyloP100

5.2

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.58

Sift

Benign

0.041

Sift4G

Benign

0.092

Polyphen

0.96

Vest4

0.26

MutPred

0.44

Loss of loop (P = 0.1242)

MVP

0.78

MPC

1.1

ClinPred

0.25

GERP RS

5.0

Varity_R

0.66

gMVP

0.83

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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