X-22168313-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM5BP6BS2_Supporting

The NM_000444.6(PHEX):c.1406C>T(p.Ala469Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000822 in 1,179,772 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 30 hemizygotes in GnomAD. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A469E) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000080 ( 0 hom. 28 hem. )

Consequence

PHEX
NM_000444.6 missense, splice_region

Scores

Splicing: ADA: 0.3387

Clinical Significance

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

Conservation

PhyloP100: 6.07

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:

PHEX-AS1 (HGNC:):

PHEX-AS1 links:

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

PHEX-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000444.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-22168313-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP6

Variant X-22168313-C-T is Benign according to our data. Variant chrX-22168313-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2376947.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

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.1406C>T	p.Ala469Val	missense_variant, splice_region_variant	Exon 13 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.1406C>T	p.Ala469Val	missense_variant, splice_region_variant	Exon 13 of 22	1	NM_000444.6	ENSP00000368682.4		P78562

Frequencies

GnomAD3 genomes

AF:

0.000108

AC:

AN:

111611

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

33833

show subpopulations

Gnomad AFR

AF:

0.000195

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00227

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

GnomAD3 exomes

AF:

0.000158

AC:

AN:

183147

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

67749

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00307

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000245

Gnomad OTH exome

AF:

0.000443

GnomAD4 exome

AF:

0.0000796

AC:

AN:

1068161

Hom.:

Cov.:

AF XY:

0.0000825

AC XY:

AN XY:

339545

show subpopulations

Gnomad4 AFR exome

AF:

0.000116

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00339

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000561

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000859

Gnomad4 OTH exome

AF:

0.000155

GnomAD4 genome

AF:

0.000108

AC:

AN:

111611

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

33833

show subpopulations

Gnomad4 AFR

AF:

0.000195

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00227

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000347

Hom.:

Bravo

AF:

0.000128

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jan 19, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1406C>T (p.A469V) alteration is located in exon 13 (coding exon 13) of the PHEX gene. This alteration results from a C to T substitution at nucleotide position 1406, causing the alanine (A) at amino acid position 469 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Dec 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.75

M_CAP

Pathogenic

0.80

MetaRNN

Uncertain

0.55

MetaSVM

Uncertain

-0.14

MutationAssessor

Uncertain

2.2

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

Sift4G

Benign

0.087

Polyphen

1.0

Vest4

0.65

MVP

0.86

MPC

1.1

ClinPred

0.21

GERP RS

4.8

Varity_R

0.93

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.34

dbscSNV1_RF

Benign

0.65

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over