rs3752433

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 12 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: Benign. The variant received -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 VariationId is 256167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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

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

GnomAD2 exomes AF: 0.264 AC: 47963 AN: 181989 AF XY: 0.260

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 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

African (AFR) AF: 0.468 AC: 12144 AN: 25973

American (AMR) AF: 0.135 AC: 4738 AN: 35129

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 4517 AN: 19268

East Asian (EAS) AF: 0.163 AC: 4891 AN: 30089

South Asian (SAS) AF: 0.180 AC: 9696 AN: 53756

European-Finnish (FIN) AF: 0.324 AC: 13097 AN: 40445

Middle Eastern (MID) AF: 0.302 AC: 1201 AN: 3974

European-Non Finnish (NFE) AF: 0.308 AC: 254196 AN: 825199

Other (OTH) AF: 0.296 AC: 13426 AN: 45392

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

African (AFR) AF: 0.449 AC: 13629 AN: 30366

American (AMR) AF: 0.215 AC: 2252 AN: 10479

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 660 AN: 2625

East Asian (EAS) AF: 0.159 AC: 562 AN: 3527

South Asian (SAS) AF: 0.191 AC: 506 AN: 2651

European-Finnish (FIN) AF: 0.315 AC: 1830 AN: 5817

Middle Eastern (MID) AF: 0.362 AC: 76 AN: 210

European-Non Finnish (NFE) AF: 0.309 AC: 16317 AN: 52837

Other (OTH) AF: 0.317 AC: 476 AN: 1500

Alfa AF: 0.307 Hom.: 18702

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

Aug 02, 2017

Athena Diagnostics

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). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		0.092
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3752433; hg19: chrX-22239720; COSMIC: COSV65079356;