X-22032898-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000444.6(PHEX):c.-108A>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 0.00357 in 589,943 control chromosomes in the GnomAD database, including 34 homozygotes. There are 527 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (22 hom., 327 hem., cov: 22)
  • Exomes 𝑓: 0.0016 (12 hom. 200 hem.)
• Consequence: PHEX NM_000444.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.299

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-22032898-A-G is Benign according to our data. Variant chrX-22032898-A-G is described in ClinVar as [Benign]. Clinvar id is 368154.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.012 (1334/111619) while in subpopulation AFR AF= 0.041 (1259/30670). AF 95% confidence interval is 0.0392. There are 22 homozygotes in gnomad4. There are 327 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHEX	NM_000444.6	c.-108A>G		5_prime_UTR_variant	1/22	ENST00000379374.5
PHEX	NM_001282754.2	c.-108A>G		5_prime_UTR_variant	1/21
PHEX	XM_047442159.1	c.-108A>G		5_prime_UTR_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHEX	ENST00000379374.5	c.-108A>G		5_prime_UTR_variant	1/22	1	NM_000444.6	P1
PHEX	ENST00000684143.1	c.-108A>G		5_prime_UTR_variant	1/11
PHEX	ENST00000475778.2	n.319A>G		non_coding_transcript_exon_variant	1/9	5
PHEX	ENST00000683214.1	n.319A>G		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1331 AN: 111566 Hom.: 22 Cov.: 22 AF XY: 0.00963 AC XY: 325 AN XY: 33734

Gnomad AFR AF: 0.0410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00460

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000377

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000940

Gnomad OTH AF: 0.0140

GnomAD4 exome AF: 0.00162 AC: 774 AN: 478324 Hom.: 12 Cov.: 7 AF XY: 0.00118 AC XY: 200 AN XY: 169480

Gnomad4 AFR exome AF: 0.0405

Gnomad4 AMR exome AF: 0.00269

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000756

Gnomad4 OTH exome AF: 0.00291

GnomAD4 genome AF: 0.0120 AC: 1334 AN: 111619 Hom.: 22 Cov.: 22 AF XY: 0.00968 AC XY: 327 AN XY: 33797

Gnomad4 AFR AF: 0.0410

Gnomad4 AMR AF: 0.00460

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000379

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000940

Gnomad4 OTH AF: 0.0138

Alfa AF: 0.00897 Hom.: 23

Bravo AF: 0.0137

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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	-0.80
Cadd	Benign	5.2
Dann	Benign	0.71

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: rs149541983; hg19: chrX-22051016;