Variant rs3752433 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Variant links:

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]

PHEX links:

PTCHD1-AS (HGNC:37703): (PTCHD1 antisense RNA (head to head))

PTCHD1-AS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
PHEX	NM_000444.6 link	c.1769-10C>T		intron_variant		ENST00000379374.5	NP_000435.3	P78562B4DWG8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHEX	ENST00000379374.5 link	c.1769-10C>T		intron_variant		1	NM_000444.6	ENSP00000368682.4		P78562

Frequencies

GnomAD3 genomes

AF:

0.331

AC:

36569

AN:

110633

Hom.:

4767

Cov.:

AF XY:

0.313

AC XY:

10295

AN XY:

32913

show subpopulations

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

show subpopulations

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.:

AF XY:

0.285

AC XY:

99557

AN XY:

349525

show subpopulations

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.:

AF XY:

0.313

AC XY:

10316

AN XY:

32977

show subpopulations

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

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	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). -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Familial X-linked hypophosphatemic vitamin D refractory rickets

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over