rs147859619

chrX-22033015-G-AchrX-22033015-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHEX	NM_000444.6	c.10G>A	p.Glu4Lys	missense_variant	1/22	ENST00000379374.5
PHEX	NM_001282754.2	c.10G>A	p.Glu4Lys	missense_variant	1/21
PHEX	XM_047442159.1	c.10G>A	p.Glu4Lys	missense_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHEX	ENST00000379374.5	c.10G>A	p.Glu4Lys	missense_variant	1/22	1	NM_000444.6	P1
PHEX	ENST00000684143.1	c.10G>A	p.Glu4Lys	missense_variant	1/11
PHEX	ENST00000475778.2	n.436G>A		non_coding_transcript_exon_variant	1/9	5
PHEX	ENST00000683214.1	n.436G>A		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 110503 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 32715 FAILED QC

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D;D
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
Varity_R		0.28
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs147859619; hg19: chrX-22051133;