chrX-22032880-C-G

Position:

chrX-22032880-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_000444.6(PHEX):c.-126C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 552,502 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 44 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., 32 hem., cov: 22)

Exomes 𝑓: 0.000079 ( 0 hom. 12 hem. )

Consequence

PHEX
NM_000444.6 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.899

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant X-22032880-C-G is Benign according to our data. Variant chrX-22032880-C-G is described in ClinVar as [Benign]. Clinvar id is 914503.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000762 (85/111481) while in subpopulation AFR AF= 0.00274 (84/30676). AF 95% confidence interval is 0.00227. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 32 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE	Protein
PHEX	NM_000444.6 linkuse as main transcript	c.-126C>G	5_prime_UTR_variant	1/22	ENST00000379374.5	NP_000435.3
PHEX	NM_001282754.2 linkuse as main transcript	c.-126C>G	5_prime_UTR_variant	1/21		NP_001269683.1
PHEX	XM_047442159.1 linkuse as main transcript	c.-126C>G	5_prime_UTR_variant	1/13		XP_047298115.1

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	Appris
PHEX	ENST00000379374.5 linkuse as main transcript	c.-126C>G	5_prime_UTR_variant	1/22	1	NM_000444.6	ENSP00000368682	P1
PHEX	ENST00000684143.1 linkuse as main transcript	c.-126C>G	5_prime_UTR_variant	1/11			ENSP00000508264
PHEX	ENST00000475778.2 linkuse as main transcript	n.301C>G	non_coding_transcript_exon_variant	1/9	5
PHEX	ENST00000683214.1 linkuse as main transcript	n.301C>G	non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes

AF:

0.000727

AC:

AN:

111431

Hom.:

Cov.:

AF XY:

0.000834

AC XY:

AN XY:

33593

show subpopulations

Gnomad AFR

AF:

0.00261

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000671

GnomAD4 exome

AF:

0.0000794

AC:

AN:

441021

Hom.:

Cov.:

AF XY:

0.0000790

AC XY:

AN XY:

151899

show subpopulations

Gnomad4 AFR exome

AF:

0.00233

Gnomad4 AMR exome

AF:

0.0000640

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:

0.0000839

GnomAD4 genome

AF:

0.000762

AC:

AN:

111481

Hom.:

Cov.:

AF XY:

0.000951

AC XY:

AN XY:

33653

show subpopulations

Gnomad4 AFR

AF:

0.00274

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000663

Alfa

AF:

0.000783

Hom.:

Bravo

AF:

0.000691

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

-0.90

CADD

Benign

4.7

DANN

Benign

0.53

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

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