X-22032973-C-T

Variant names:

• chrX-22032973-C-T
• rs5951494
• NM_000444.6:c.-33C>T

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: 0.303
• 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: Labcorp Genetics (formerly Invitae), Illumina, Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 368156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.194 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	NM_000444.6	MANE Select	c.-33C>T		5_prime_UTR	Exon 1 of 22	NP_000435.3
	PHEX	NM_001282754.2		c.-33C>T		5_prime_UTR	Exon 1 of 21	NP_001269683.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	ENST00000379374.5	TSL:1 MANE Select	c.-33C>T		5_prime_UTR	Exon 1 of 22	ENSP00000368682.4	P78562
	PHEX	ENST00000684143.1		c.-33C>T		5_prime_UTR	Exon 1 of 11	ENSP00000508264.1	A0A804HLA0
	PHEX	ENST00000475778.2	TSL:5	n.394C>T		non_coding_transcript_exon	Exon 1 of 9

Frequencies

GnomAD3 genomes AF: 0.126 AC: 13983 AN: 110714 Hom.: 722 Cov.: 22

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

GnomAD2 exomes AF: 0.0932 AC: 17069 AN: 183229 AF XY: 0.0897

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 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

African (AFR) AF: 0.215 AC: 5232 AN: 24311

American (AMR) AF: 0.0508 AC: 1781 AN: 35090

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 2535 AN: 18714

East Asian (EAS) AF: 0.000303 AC: 9 AN: 29704

South Asian (SAS) AF: 0.0479 AC: 2484 AN: 51874

European-Finnish (FIN) AF: 0.107 AC: 4338 AN: 40458

Middle Eastern (MID) AF: 0.104 AC: 391 AN: 3746

European-Non Finnish (NFE) AF: 0.113 AC: 83727 AN: 741295

Other (OTH) AF: 0.110 AC: 4687 AN: 42463

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

African (AFR) AF: 0.198 AC: 6018 AN: 30358

American (AMR) AF: 0.0746 AC: 773 AN: 10368

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 331 AN: 2643

East Asian (EAS) AF: 0.000283 AC: 1 AN: 3538

South Asian (SAS) AF: 0.0436 AC: 113 AN: 2593

European-Finnish (FIN) AF: 0.106 AC: 629 AN: 5957

Middle Eastern (MID) AF: 0.0922 AC: 20 AN: 217

European-Non Finnish (NFE) AF: 0.111 AC: 5874 AN: 52910

Other (OTH) AF: 0.114 AC: 171 AN: 1506

Alfa AF: 0.118 Hom.: 4518

Bravo AF: 0.129

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Familial X-linked hypophosphatemic vitamin D refractory rickets (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.87
PhyloP100		0.30
PromoterAI		-0.0012	Neutral
Mutation Taster		=300/0	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: rs5951494; hg19: chrX-22051091; COSMIC: COSV65075366;