X-22033063-C-G

Variant names:

• chrX-22033063-C-G
• rs770573978
• NM_000444.6:c.58C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4 BS2_Supporting

The NM_000444.6(PHEX):​c.58C>G​(p.Arg20Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000456 in 1,097,494 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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: not found (cov: 22)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: PHEX NM_000444.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.74

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.38077623).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHEX	NM_000444.6	c.58C>G	p.Arg20Gly	missense_variant	Exon 1 of 22	ENST00000379374.5	NP_000435.3
PHEX	NM_001282754.2	c.58C>G	p.Arg20Gly	missense_variant	Exon 1 of 21		NP_001269683.1
PHEX	XM_047442159.1	c.58C>G	p.Arg20Gly	missense_variant	Exon 1 of 13		XP_047298115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHEX	ENST00000379374.5	c.58C>G	p.Arg20Gly	missense_variant	Exon 1 of 22	1	NM_000444.6	ENSP00000368682.4
PHEX	ENST00000684143.1	c.58C>G	p.Arg20Gly	missense_variant	Exon 1 of 11			ENSP00000508264.1
PHEX	ENST00000475778.2	n.484C>G		non_coding_transcript_exon_variant	Exon 1 of 9	5
PHEX	ENST00000683214.1	n.484C>G		non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 183108 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67614

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1097494 Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 2 AN XY: 362860

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000924

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.00041	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.51
Sift	Benign	0.041	D
Sift4G	Benign	0.29	T
Polyphen		0.18	B
Vest4		0.19
MutPred		0.66		Loss of MoRF binding (P = 0.0045);
MVP		0.74
MPC		0.54
ClinPred		0.14	T
GERP RS		4.0
Varity_R		0.23
gMVP		0.75

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: rs770573978; hg19: chrX-22051181;