X-22033018-A-T

Variant names:

• chrX-22033018-A-T
• NM_000444.6:c.13A>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000444.6(PHEX):​c.13A>T​(p.Thr5Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: PHEX NM_000444.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.250

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03191918).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHEX	NM_000444.6	c.13A>T	p.Thr5Ser	missense_variant	Exon 1 of 22	ENST00000379374.5	NP_000435.3
PHEX	NM_001282754.2	c.13A>T	p.Thr5Ser	missense_variant	Exon 1 of 21		NP_001269683.1
PHEX	XM_047442159.1	c.13A>T	p.Thr5Ser	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.13A>T	p.Thr5Ser	missense_variant	Exon 1 of 22	1	NM_000444.6	ENSP00000368682.4
PHEX	ENST00000684143.1	c.13A>T	p.Thr5Ser	missense_variant	Exon 1 of 11			ENSP00000508264.1
PHEX	ENST00000475778.2	n.439A>T		non_coding_transcript_exon_variant	Exon 1 of 9	5
PHEX	ENST00000683214.1	n.439A>T		non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 5 of the PHEX protein (p.Thr5Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PHEX-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PHEX protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	4.1
DANN	Benign	0.83
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.6	L
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.21
Sift	Benign	0.26	T
Sift4G	Benign	0.62	T
Polyphen		0.0080	B
Vest4		0.045
MutPred		0.067		Gain of phosphorylation at T5 (P = 0.0317);
MVP		0.27
MPC		0.34
ClinPred		0.11	T
GERP RS		-4.8
Varity_R		0.052
gMVP		0.49

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-22051136;