X-22033018-A-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP2 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. 16/21 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
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 135 curated pathogenic missense variants (we use a threshold of 10). The gene has 25 curated benign missense variants. Gene score misZ: 1.7091 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked dominant hypophosphatemic rickets.
• BP4: Computational evidence support a benign effect (MetaRNN=0.03191918).

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.13A>T	p.Thr5Ser	missense	Exon 1 of 22	NP_000435.3
	PHEX	NM_001282754.2		c.13A>T	p.Thr5Ser	missense	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.13A>T	p.Thr5Ser	missense	Exon 1 of 22	ENSP00000368682.4	P78562
	PHEX	ENST00000684143.1		c.13A>T	p.Thr5Ser	missense	Exon 1 of 11	ENSP00000508264.1	A0A804HLA0
	PHEX	ENST00000475778.2	TSL:5	n.439A>T		non_coding_transcript_exon	Exon 1 of 9

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.25
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
PromoterAI		-0.030	Neutral
Varity_R		0.052
gMVP		0.49
Mutation Taster		=96/4	polymorphism

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

hg19: chrX-22051136;