Genetic Variant NM_000444.6:c.871C>T (chrX-22096976-C-T) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000444.6(PHEX):c.871C>T(p.Arg291*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

PHEX
NM_000444.6 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 1.79

Publications

11 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: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant X-22096976-C-T is Pathogenic according to our data. Variant chrX-22096976-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 372454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.871C>T	p.Arg291*	stop_gained	Exon 8 of 22	NP_000435.3
	PHEX	NM_001282754.2		c.871C>T	p.Arg291*	stop_gained	Exon 8 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.871C>T	p.Arg291*	stop_gained	Exon 8 of 22	ENSP00000368682.4	P78562
PHEX	ENST00000684143.1		c.868C>T	p.Arg290*	stop_gained	Exon 8 of 11	ENSP00000508264.1	A0A804HLA0
PHEX	ENST00000475778.2	TSL:5	n.1297C>T		non_coding_transcript_exon	Exon 8 of 9

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

111127

Hom.:

Cov.:

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

183345

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1090055

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

356019

African (AFR)

AF:

0.00

AC:

AN:

26231

American (AMR)

AF:

0.00

AC:

AN:

35184

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19303

East Asian (EAS)

AF:

0.00

AC:

AN:

30107

South Asian (SAS)

AF:

0.00

AC:

AN:

53957

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40493

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4104

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

834899

Other (OTH)

AF:

0.00

AC:

AN:

45777

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

111127

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33449

African (AFR)

AF:

0.00

AC:

AN:

30560

American (AMR)

AF:

0.00

AC:

AN:

10507

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3533

South Asian (SAS)

AF:

0.00

AC:

AN:

2617

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5943

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52916

Other (OTH)

AF:

0.00

AC:

AN:

1492

Alfa

AF:

0.0000412

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial X-linked hypophosphatemic vitamin D refractory rickets (6)

not provided (3)

Hypophosphatemic rickets (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Uncertain

0.88

PhyloP100

1.8

Vest4

0.95

GERP RS

5.2

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over