X-22032916-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000444.6(PHEX):c.-90A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (11464 hom., 16574 hem., cov: 22)
  • Exomes 𝑓: 0.46 (39380 hom. 81893 hem.)
  • Failed GnomAD Quality Control
• Consequence: PHEX NM_000444.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.55

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant X-22032916-A-G is Benign according to our data. Variant chrX-22032916-A-G is described in ClinVar as [Benign]. Clinvar id is 368155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.687 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHEX	NM_000444.6	c.-90A>G		5_prime_UTR_variant	1/22	ENST00000379374.5
PHEX	NM_001282754.2	c.-90A>G		5_prime_UTR_variant	1/21
PHEX	XM_047442159.1	c.-90A>G		5_prime_UTR_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHEX	ENST00000379374.5	c.-90A>G		5_prime_UTR_variant	1/22	1	NM_000444.6	P1
PHEX	ENST00000684143.1	c.-90A>G		5_prime_UTR_variant	1/11
PHEX	ENST00000475778.2	n.337A>G		non_coding_transcript_exon_variant	1/9	5
PHEX	ENST00000683214.1	n.337A>G		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes AF: 0.524 AC: 57831 AN: 110312 Hom.: 11457 Cov.: 22 AF XY: 0.508 AC XY: 16533 AN XY: 32538

Gnomad AFR AF: 0.696

Gnomad AMI AF: 0.371

Gnomad AMR AF: 0.514

Gnomad ASJ AF: 0.467

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.419

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.495

GnomAD4 exome AF: 0.461 AC: 247570 AN: 537030 Hom.: 39380 Cov.: 8 AF XY: 0.454 AC XY: 81893 AN XY: 180454

Gnomad4 AFR exome AF: 0.698

Gnomad4 AMR exome AF: 0.522

Gnomad4 ASJ exome AF: 0.459

Gnomad4 EAS exome AF: 0.356

Gnomad4 SAS exome AF: 0.394

Gnomad4 FIN exome AF: 0.440

Gnomad4 NFE exome AF: 0.463

Gnomad4 OTH exome AF: 0.476

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.524 AC: 57880 AN: 110366 Hom.: 11464 Cov.: 22 AF XY: 0.508 AC XY: 16574 AN XY: 32602

Gnomad4 AFR AF: 0.696

Gnomad4 AMR AF: 0.513

Gnomad4 ASJ AF: 0.467

Gnomad4 EAS AF: 0.362

Gnomad4 SAS AF: 0.401

Gnomad4 FIN AF: 0.419

Gnomad4 NFE AF: 0.463

Gnomad4 OTH AF: 0.499

Alfa AF: 0.486 Hom.: 23088

Bravo AF: 0.541

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial X-linked hypophosphatemic vitamin D refractory rickets Benign:1

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	-0.74
Cadd	Benign	12
Dann	Benign	0.92

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: rs178710; hg19: chrX-22051034; COSMIC: COSV65073907;