chrX-22142875-G-A

Variant names:

• chrX-22142875-G-A
• rs12559632
• NM_000444.6:c.1404+9251G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000444.6(PHEX):​c.1404+9251G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 111,648 control chromosomes in the GnomAD database, including 2,777 homozygotes. There are 8,419 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (2777 hom., 8419 hem., cov: 23)
• Consequence: PHEX NM_000444.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0700
• Publications: 8 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: Illumina, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHEX	NM_000444.6	c.1404+9251G>A		intron_variant	Intron 12 of 21	ENST00000379374.5	NP_000435.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHEX	ENST00000379374.5	c.1404+9251G>A		intron_variant	Intron 12 of 21	1	NM_000444.6	ENSP00000368682.4

Frequencies

GnomAD3 genomes AF: 0.259 AC: 28863 AN: 111594 Hom.: 2769 Cov.: 23

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.450

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.274

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.259 AC: 28874 AN: 111648 Hom.: 2777 Cov.: 23 AF XY: 0.249 AC XY: 8419 AN XY: 33854

African (AFR) AF: 0.252 AC: 7774 AN: 30794

American (AMR) AF: 0.268 AC: 2820 AN: 10541

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 785 AN: 2644

East Asian (EAS) AF: 0.450 AC: 1577 AN: 3501

South Asian (SAS) AF: 0.248 AC: 668 AN: 2694

European-Finnish (FIN) AF: 0.199 AC: 1202 AN: 6035

Middle Eastern (MID) AF: 0.325 AC: 69 AN: 212

European-Non Finnish (NFE) AF: 0.253 AC: 13407 AN: 53040

Other (OTH) AF: 0.278 AC: 420 AN: 1512

Alfa AF: 0.265 Hom.: 31654

Bravo AF: 0.271

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.2
DANN	Benign	0.72
PhyloP100		-0.070
Mutation Taster		=100/0	polymorphism (auto)

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: rs12559632; hg19: chrX-22160992;