chrX-22221603-C-T

Variant names:

• chrX-22221603-C-T
• rs3752433
• NM_000444.6:c.1769-10C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000444.6(PHEX):​c.1769-10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 1,189,912 control chromosomes in the GnomAD database, including 39,137 homozygotes. There are 109,873 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (4773 hom., 10316 hem., cov: 22)
  • Exomes 𝑓: 0.29 (34364 hom. 99557 hem.)
• Consequence: PHEX NM_000444.6 intron
• Scores: Splicing: ADA: 0.00003442
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0920

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-22221603-C-T is Benign according to our data. Variant chrX-22221603-C-T is described in ClinVar as [Benign]. Clinvar id is 256167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-22221603-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.443 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHEX	NM_000444.6	c.1769-10C>T		intron_variant	Intron 17 of 21	ENST00000379374.5	NP_000435.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHEX	ENST00000379374.5	c.1769-10C>T		intron_variant	Intron 17 of 21	1	NM_000444.6	ENSP00000368682.4

Frequencies

GnomAD3 genomes AF: 0.331 AC: 36569 AN: 110633 Hom.: 4767 Cov.: 22 AF XY: 0.313 AC XY: 10295 AN XY: 32913

Gnomad AFR AF: 0.449

Gnomad AMI AF: 0.437

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.319

GnomAD3 exomes AF: 0.264 AC: 47963 AN: 181989 Hom.: 4698 AF XY: 0.260 AC XY: 17388 AN XY: 66829

Gnomad AFR exome AF: 0.454

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.235

Gnomad EAS exome AF: 0.170

Gnomad SAS exome AF: 0.173

Gnomad FIN exome AF: 0.319

Gnomad NFE exome AF: 0.307

Gnomad OTH exome AF: 0.291

GnomAD4 exome AF: 0.295 AC: 317906 AN: 1079225 Hom.: 34364 Cov.: 27 AF XY: 0.285 AC XY: 99557 AN XY: 349525

Gnomad4 AFR exome AF: 0.468

Gnomad4 AMR exome AF: 0.135

Gnomad4 ASJ exome AF: 0.234

Gnomad4 EAS exome AF: 0.163

Gnomad4 SAS exome AF: 0.180

Gnomad4 FIN exome AF: 0.324

Gnomad4 NFE exome AF: 0.308

Gnomad4 OTH exome AF: 0.296

GnomAD4 genome AF: 0.331 AC: 36603 AN: 110687 Hom.: 4773 Cov.: 22 AF XY: 0.313 AC XY: 10316 AN XY: 32977

Gnomad4 AFR AF: 0.449

Gnomad4 AMR AF: 0.215

Gnomad4 ASJ AF: 0.251

Gnomad4 EAS AF: 0.159

Gnomad4 SAS AF: 0.191

Gnomad4 FIN AF: 0.315

Gnomad4 NFE AF: 0.309

Gnomad4 OTH AF: 0.317

Alfa AF: 0.302 Hom.: 14260

Bravo AF: 0.330

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.1769-10C>T in intron 17 of PHEX: This variant is not expected to have clinical significance because a C>T change at this position does not diverge from the sp lice consensus sequence and is therefore unlikely to impact splicing. It has bee n identified in 44.62% (3722/8342) of African chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs3752433). -

Aug 02, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial X-linked hypophosphatemic vitamin D refractory rickets Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.8
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.040		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: rs3752433; hg19: chrX-22239720; COSMIC: COSV65079356;