rs748792378

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1PM5PP2BS2_Supporting

The NM_000444.6(PHEX):c.1952G>A(p.Arg651Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000791 in 1,200,938 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 40 hemizygotes in GnomAD. 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. R651P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000055 ( 0 hom., 2 hem., cov: 21)

Exomes 𝑓: 0.000082 ( 0 hom. 38 hem. )

Consequence

PHEX
NM_000444.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.04

Publications

6 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000444.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-22226495-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 438548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

BS2

High Hemizygotes in GnomAd4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHEX	NM_000444.6 link	c.1952G>A	p.Arg651Gln	missense_variant	Exon 19 of 22	ENST00000379374.5	NP_000435.3	P78562B4DWG8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHEX	ENST00000379374.5 link	c.1952G>A	p.Arg651Gln	missense_variant	Exon 19 of 22	1	NM_000444.6	ENSP00000368682.4		P78562

Frequencies

GnomAD3 genomes

AF:

0.0000550

AC:

AN:

109054

Hom.:

Cov.:

show subpopulations

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:

0.00121

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000571

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000382

AC:

AN:

183443

AF XY:

0.0000589

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000244

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000815

AC:

AN:

1091884

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

357496

show subpopulations

African (AFR)

AF:

0.0000761

AC:

AN:

26291

American (AMR)

AF:

0.00

AC:

AN:

35201

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19339

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30171

South Asian (SAS)

AF:

0.000315

AC:

AN:

53999

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40517

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4120

European-Non Finnish (NFE)

AF:

0.0000777

AC:

AN:

836348

Other (OTH)

AF:

0.0000871

AC:

AN:

45898

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

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:

0.0000550

AC:

AN:

109054

Hom.:

Cov.:

AF XY:

0.0000637

AC XY:

AN XY:

31390

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29825

American (AMR)

AF:

0.00

AC:

AN:

10174

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2619

East Asian (EAS)

AF:

0.00

AC:

AN:

3456

South Asian (SAS)

AF:

0.00121

AC:

AN:

2479

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

235

European-Non Finnish (NFE)

AF:

0.0000571

AC:

AN:

52504

Other (OTH)

AF:

0.00

AC:

AN:

1463

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.00

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.67

MetaRNN

Uncertain

0.52

MetaSVM

Uncertain

0.22

MutationAssessor

Benign

1.4

PhyloP100

8.0

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-2.1

REVEL

Pathogenic

0.77

Sift

Uncertain

0.018

Sift4G

Uncertain

0.020

Polyphen

1.0

Vest4

0.22

MVP

0.94

MPC

1.3

ClinPred

0.44

GERP RS

5.9

Varity_R

0.79

gMVP

0.79

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over