rs2269466

Variant names:

• chrX-22137307-T-C
• rs2269466
• NM_000444.6:c.1404+3683T>C

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+3683T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 111,037 control chromosomes in the GnomAD database, including 2,521 homozygotes. There are 7,154 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 0.22 (2521 hom., 7154 hem., cov: 22)
• Consequence: PHEX NM_000444.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.904
• Publications: 4 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

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.1404+3683T>C		intron	N/A	NP_000435.3
	PHEX	NM_001282754.2		c.1404+3683T>C		intron	N/A	NP_001269683.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	ENST00000379374.5	TSL:1 MANE Select	c.1404+3683T>C		intron	N/A	ENSP00000368682.4
	PHEX	ENST00000684356.1		c.-204+646T>C		intron	N/A	ENSP00000507619.1
	PHEX	ENST00000682888.1		c.-43+642T>C		intron	N/A	ENSP00000508003.1

Frequencies

GnomAD3 genomes AF: 0.224 AC: 24912 AN: 110985 Hom.: 2522 Cov.: 22

Gnomad AFR AF: 0.0551

Gnomad AMI AF: 0.336

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.254

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

GnomAD4 genome AF: 0.224 AC: 24908 AN: 111037 Hom.: 2521 Cov.: 22 AF XY: 0.215 AC XY: 7154 AN XY: 33291

African (AFR) AF: 0.0550 AC: 1688 AN: 30677

American (AMR) AF: 0.257 AC: 2686 AN: 10456

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 852 AN: 2634

East Asian (EAS) AF: 0.279 AC: 973 AN: 3489

South Asian (SAS) AF: 0.158 AC: 416 AN: 2628

European-Finnish (FIN) AF: 0.251 AC: 1483 AN: 5914

Middle Eastern (MID) AF: 0.341 AC: 73 AN: 214

European-Non Finnish (NFE) AF: 0.305 AC: 16133 AN: 52850

Other (OTH) AF: 0.252 AC: 379 AN: 1505

Alfa AF: 0.285 Hom.: 17552

Bravo AF: 0.223

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.6
DANN	Benign	0.44
PhyloP100		0.90
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: rs2269466; hg19: chrX-22155424;