chrX-22168355-T-C

Position:

• chrX-22168355-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000444.6(PHEX):​c.1448T>C​(p.Met483Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000926 in 1,079,675 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: PHEX NM_000444.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.36

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-AS1 (HGNC:40445): (PHEX antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHEX	NM_000444.6	c.1448T>C	p.Met483Thr	missense_variant	13/22	ENST00000379374.5	NP_000435.3
PHEX-AS1	NR_046639.1	n.1267+1439A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHEX	ENST00000379374.5	c.1448T>C	p.Met483Thr	missense_variant	13/22	1	NM_000444.6	ENSP00000368682	P1
PHEX-AS1	ENST00000424650.1	n.1267+1439A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.26e-7 AC: 1 AN: 1079675 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 346209

Gnomad4 AFR exome AF: 0.0000384

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2023

The c.1448T>C (p.M483T) alteration is located in exon 13 (coding exon 13) of the PHEX gene. This alteration results from a T to C substitution at nucleotide position 1448, causing the methionine (M) at amino acid position 483 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	23
DANN	Benign	0.87
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	0.96	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.93	N
REVEL	Uncertain	0.51
Sift	Benign	0.51	T
Sift4G	Benign	0.45	T
Polyphen		0.54	P
Vest4		0.56
MutPred		0.78		Loss of stability (P = 0.039);
MVP		0.92
MPC		0.44
ClinPred		0.57	D
GERP RS		5.0
Varity_R		0.59
gMVP		0.86

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-22186472;