X-22033049-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Moderate BP6_Moderate

The NM_000444.6(PHEX):c.44C>G(p.Ala15Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000283 in 1,097,100 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000028 (0 hom. 9 hem.)
• Consequence: PHEX NM_000444.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.26

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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19915733).
• BP6: Variant X-22033049-C-G is Benign according to our data. Variant chrX-22033049-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2909415.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHEX	NM_000444.6	c.44C>G	p.Ala15Gly	missense_variant	1/22	ENST00000379374.5
PHEX	NM_001282754.2	c.44C>G	p.Ala15Gly	missense_variant	1/21
PHEX	XM_047442159.1	c.44C>G	p.Ala15Gly	missense_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHEX	ENST00000379374.5	c.44C>G	p.Ala15Gly	missense_variant	1/22	1	NM_000444.6	P1
PHEX	ENST00000684143.1	c.44C>G	p.Ala15Gly	missense_variant	1/11
PHEX	ENST00000475778.2	n.470C>G		non_coding_transcript_exon_variant	1/9	5
PHEX	ENST00000683214.1	n.470C>G		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000164 AC: 3 AN: 183253 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67713

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000283 AC: 31 AN: 1097100 Hom.: 0 Cov.: 29 AF XY: 0.0000248 AC XY: 9 AN XY: 362490

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	14
Dann	Uncertain	0.99
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.9	M
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.54	N
REVEL	Uncertain	0.29
Sift	Benign	0.049	D
Sift4G	Benign	0.16	T
Polyphen		0.037	B
Vest4		0.11
MutPred		0.12		Gain of disorder (P = 0.0798);
MVP		0.64
MPC		0.37
ClinPred		0.13	T
GERP RS		5.8
Varity_R		0.14
gMVP		0.47

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: rs773033853; hg19: chrX-22051167;