X-22032973-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000444.6(PHEX):c.-33C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,098,422 control chromosomes in the GnomAD database, including 5,045 homozygotes. There are 34,630 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (724 hom., 3795 hem., cov: 22)
  • Exomes 𝑓: 0.11 (4321 hom. 30835 hem.)
• Consequence: PHEX NM_000444.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.303

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant X-22032973-C-T is Benign according to our data. Variant chrX-22032973-C-T is described in ClinVar as [Benign]. Clinvar id is 368156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-22032973-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHEX	NM_000444.6	c.-33C>T		5_prime_UTR_variant	1/22	ENST00000379374.5
PHEX	NM_001282754.2	c.-33C>T		5_prime_UTR_variant	1/21
PHEX	XM_047442159.1	c.-33C>T		5_prime_UTR_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHEX	ENST00000379374.5	c.-33C>T		5_prime_UTR_variant	1/22	1	NM_000444.6	P1
PHEX	ENST00000684143.1	c.-33C>T		5_prime_UTR_variant	1/11
PHEX	ENST00000475778.2	n.394C>T		non_coding_transcript_exon_variant	1/9	5
PHEX	ENST00000683214.1	n.394C>T		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes AF: 0.126 AC: 13983 AN: 110714 Hom.: 722 Cov.: 22 AF XY: 0.115 AC XY: 3787 AN XY: 32942

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.0871

Gnomad AMR AF: 0.0747

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.000282

Gnomad SAS AF: 0.0423

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.105

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.115

GnomAD3 exomes AF: 0.0932 AC: 17069 AN: 183229 Hom.: 724 AF XY: 0.0897 AC XY: 6072 AN XY: 67701

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.0456

Gnomad ASJ exome AF: 0.138

Gnomad EAS exome AF: 0.000289

Gnomad SAS exome AF: 0.0443

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.106 AC: 105184 AN: 987655 Hom.: 4321 Cov.: 20 AF XY: 0.105 AC XY: 30835 AN XY: 294189

Gnomad4 AFR exome AF: 0.215

Gnomad4 AMR exome AF: 0.0508

Gnomad4 ASJ exome AF: 0.135

Gnomad4 EAS exome AF: 0.000303

Gnomad4 SAS exome AF: 0.0479

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.113

Gnomad4 OTH exome AF: 0.110

GnomAD4 genome AF: 0.126 AC: 13989 AN: 110767 Hom.: 724 Cov.: 22 AF XY: 0.115 AC XY: 3795 AN XY: 33005

Gnomad4 AFR AF: 0.198

Gnomad4 AMR AF: 0.0746

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.000283

Gnomad4 SAS AF: 0.0436

Gnomad4 FIN AF: 0.106

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.114

Alfa AF: 0.114 Hom.: 3221

Bravo AF: 0.129

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial X-linked hypophosphatemic vitamin D refractory rickets Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	14
Dann	Benign	0.87

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: rs5951494; hg19: chrX-22051091; COSMIC: COSV65075366;