rs1556151526

Variant names:

• chrX-22227581-C-A
• rs1556151526
• NM_000444.6:c.2040C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000444.6(PHEX):​c.2040C>A​(p.Asn680Lys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PHEX NM_000444.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.04
• 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))

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000444.6
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879

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.2040C>A	p.Asn680Lys	missense	Exon 20 of 22	NP_000435.3
	PHEX	NM_001282754.2		c.2040C>A	p.Asn680Lys	missense	Exon 20 of 21	NP_001269683.1
	PTCHD1-AS	NR_073010.2		n.937G>T		non_coding_transcript_exon	Exon 9 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	ENST00000379374.5	TSL:1 MANE Select	c.2040C>A	p.Asn680Lys	missense	Exon 20 of 22	ENSP00000368682.4	P78562
	PHEX	ENST00000684356.1		c.594C>A	p.Asn198Lys	missense	Exon 10 of 12	ENSP00000507619.1	A0A804HJR7
	PTCHD1-AS	ENST00000669979.1		n.214G>T		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1091118 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 356778

African (AFR) AF: 0.00 AC: 0 AN: 26254

American (AMR) AF: 0.00 AC: 0 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19333

East Asian (EAS) AF: 0.00 AC: 0 AN: 30173

South Asian (SAS) AF: 0.00 AC: 0 AN: 53969

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4118

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 835674

Other (OTH) AF: 0.00 AC: 0 AN: 45870

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)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.7	L
PhyloP100		2.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.12	T
Polyphen		0.97	D
Vest4		0.42
MutPred		0.81		Gain of ubiquitination at N680 (P = 0.0289)
MVP		0.90
MPC		0.74
ClinPred		0.88	D
GERP RS		5.4
Varity_R		0.71
gMVP		0.76
Mutation Taster		=7/93	disease causing

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

dbSNP: rs1556151526; hg19: chrX-22245698; COSMIC: COSV65077567;