NM_000444.6:c.1448T>C

Variant names:

• chrX-22168355-T-C
• NM_000444.6:c.1448T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

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, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.36
• 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]

PTCHD1-AS (HGNC:37703): (PTCHD1 antisense RNA (head to head))

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 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.

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.1448T>C	p.Met483Thr	missense	Exon 13 of 22	NP_000435.3
	PHEX	NM_001282754.2		c.1448T>C	p.Met483Thr	missense	Exon 13 of 21	NP_001269683.1
	PHEX-AS1	NR_046639.1		n.1267+1439A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	ENST00000379374.5	TSL:1 MANE Select	c.1448T>C	p.Met483Thr	missense	Exon 13 of 22	ENSP00000368682.4	P78562
	PHEX	ENST00000684356.1		c.2T>C	p.Met1?	start_lost	Exon 3 of 12	ENSP00000507619.1	A0A804HJR7
	PHEX	ENST00000682888.1		c.2T>C	p.Met1?	start_lost	Exon 2 of 8	ENSP00000508003.1	A0A804HKN7

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

African (AFR) AF: 0.0000384 AC: 1 AN: 26042

American (AMR) AF: 0.00 AC: 0 AN: 35168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19262

East Asian (EAS) AF: 0.00 AC: 0 AN: 30121

South Asian (SAS) AF: 0.00 AC: 0 AN: 53722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4000

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 825380

Other (OTH) AF: 0.00 AC: 0 AN: 45468

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Familial X-linked hypophosphatemic vitamin D refractory rickets (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.4
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
Mutation Taster		=58/42	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-22186472;