rs1556135308

Variant names:

• chrX-22219053-C-A
• rs1556135308
• NM_000444.6:c.1718C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-22219053-C-A
• chrX-22219053-C-T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000444.6(PHEX):​c.1718C>A​(p.Ala573Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000938 in 1,065,546 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A573S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.4e-7 (0 hom. 0 hem.)
• Consequence: PHEX NM_000444.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.82
• 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: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000444.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-22219053-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 803763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.991
• PP5: Variant X-22219053-C-A is Pathogenic according to our data. Variant chrX-22219053-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 438578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1718C>A	p.Ala573Asp	missense	Exon 17 of 22	NP_000435.3
	PHEX	NM_001282754.2		c.1718C>A	p.Ala573Asp	missense	Exon 17 of 21	NP_001269683.1
	PTCHD1-AS	NR_073010.2		n.1048+8417G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	ENST00000379374.5	TSL:1 MANE Select	c.1718C>A	p.Ala573Asp	missense	Exon 17 of 22	ENSP00000368682.4	P78562
	PHEX	ENST00000684356.1		c.272C>A	p.Ala91Asp	missense	Exon 7 of 12	ENSP00000507619.1	A0A804HJR7
	PHEX	ENST00000682888.1		c.272C>A	p.Ala91Asp	missense	Exon 6 of 8	ENSP00000508003.1	A0A804HKN7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.38e-7 AC: 1 AN: 1065546 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 338074

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25824

American (AMR) AF: 0.00 AC: 0 AN: 35167

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19171

East Asian (EAS) AF: 0.00 AC: 0 AN: 30017

South Asian (SAS) AF: 0.00 AC: 0 AN: 53355

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4047

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 812609

Other (OTH) AF: 0.0000222 AC: 1 AN: 44988

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Familial X-linked hypophosphatemic vitamin D refractory rickets (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		6.8
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.89		Gain of phosphorylation at Y571 (P = 0.098)
MVP		0.99
MPC		1.2
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.96
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs1556135308; hg19: chrX-22237170;