X-22033061-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_000444.6(PHEX):c.56C>A(p.Thr19Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000456 in 1,097,599 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: PHEX NM_000444.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.535

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18991157).
• BP6: Variant X-22033061-C-A is Benign according to our data. Variant chrX-22033061-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 2022925.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHEX	NM_000444.6	c.56C>A	p.Thr19Asn	missense_variant	1/22	ENST00000379374.5
PHEX	NM_001282754.2	c.56C>A	p.Thr19Asn	missense_variant	1/21
PHEX	XM_047442159.1	c.56C>A	p.Thr19Asn	missense_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHEX	ENST00000379374.5	c.56C>A	p.Thr19Asn	missense_variant	1/22	1	NM_000444.6	P1
PHEX	ENST00000684143.1	c.56C>A	p.Thr19Asn	missense_variant	1/11
PHEX	ENST00000475778.2	n.482C>A		non_coding_transcript_exon_variant	1/9	5
PHEX	ENST00000683214.1	n.482C>A		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183139 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67627

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1097599 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 362953

Gnomad4 AFR exome AF: 0.000189

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.: 22

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 08, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	5.6
Dann	Benign	0.74
DEOGEN2	Benign	0.26	T
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.14
Sift	Benign	0.031	D
Sift4G	Benign	0.57	T
Polyphen		0.072	B
Vest4		0.44
MutPred		0.29		Loss of phosphorylation at T19 (P = 0.0966);
MVP		0.24
MPC		0.60
ClinPred		0.054	T
GERP RS		0.44
Varity_R		0.085
gMVP		0.67

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

LitVar

Other links and lift over

dbSNP: rs935444170; hg19: chrX-22051179;