Genetic Variant PHEX:p.Lys319Asn (chrX-22099029-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_000444.6(PHEX):c.957G>T(p.Lys319Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. K319T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Consequence

PHEX
NM_000444.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.02

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.2375423).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	NM_000444.6	MANE Select	c.957G>T	p.Lys319Asn	missense	Exon 9 of 22	NP_000435.3
	PHEX	NM_001282754.2		c.957G>T	p.Lys319Asn	missense	Exon 9 of 21	NP_001269683.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PHEX	ENST00000379374.5	TSL:1 MANE Select	c.957G>T	p.Lys319Asn	missense	Exon 9 of 22	ENSP00000368682.4
PHEX	ENST00000684143.1		c.954G>T	p.Lys318Asn	missense	Exon 9 of 11	ENSP00000508264.1
PHEX	ENST00000475778.2	TSL:5	n.1383G>T		non_coding_transcript_exon	Exon 9 of 9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.30

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.85

M_CAP

Benign

0.023

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.54

PhyloP100

3.0

PrimateAI

Uncertain

0.51

PROVEAN

Benign

0.19

REVEL

Benign

0.13

Sift

Benign

0.38

Sift4G

Benign

0.49

Polyphen

0.0030

Vest4

0.57

MutPred

0.47

Loss of methylation at K319 (P = 0.0144)

MVP

0.29

MPC

0.77

ClinPred

0.67

GERP RS

3.3

Varity_R

0.41

gMVP

0.70

Mutation Taster

=46/54

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over