X-22033015-G-A

Variant names:

• chrX-22033015-G-A
• rs147859619
• NM_000444.6:c.10G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000444.6(PHEX):​c.10G>A​(p.Glu4Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. E4Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., 0 hem., cov: 22)
  • Failed GnomAD Quality Control
• Consequence: PHEX NM_000444.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.17
• Publications: 5 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 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.

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.10G>A	p.Glu4Lys	missense	Exon 1 of 22	NP_000435.3
	PHEX	NM_001282754.2		c.10G>A	p.Glu4Lys	missense	Exon 1 of 21	NP_001269683.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	ENST00000379374.5	TSL:1 MANE Select	c.10G>A	p.Glu4Lys	missense	Exon 1 of 22	ENSP00000368682.4	P78562
	PHEX	ENST00000684143.1		c.10G>A	p.Glu4Lys	missense	Exon 1 of 11	ENSP00000508264.1	A0A804HLA0
	PHEX	ENST00000475778.2	TSL:5	n.436G>A		non_coding_transcript_exon	Exon 1 of 9

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 110503 Hom.: 0 Cov.: 22

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

GnomAD4 exome Cov.: 29

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 110503 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 32715

African (AFR) AF: 0.00 AC: 0 AN: 30293

American (AMR) AF: 0.00 AC: 0 AN: 10269

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2632

East Asian (EAS) AF: 0.00 AC: 0 AN: 3540

South Asian (SAS) AF: 0.00 AC: 0 AN: 2518

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52908

Other (OTH) AF: 0.00 AC: 0 AN: 1491

Alfa AF: 0.00 Hom.: 8

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.57	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.086	D
MutationAssessor	Benign	1.8	L
PhyloP100		6.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.070	N
REVEL	Uncertain	0.39
Sift	Benign	0.049	D
Sift4G	Uncertain	0.050	T
Polyphen		0.96	P
Vest4		0.36
MutPred		0.17		Gain of ubiquitination at E4 (P = 0.006)
MVP		0.94
MPC		1.2
ClinPred		0.78	D
GERP RS		5.8
PromoterAI		-0.020	Neutral
Varity_R		0.28
gMVP		0.84
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

dbSNP: rs147859619; hg19: chrX-22051133;