X-22032898-A-G

Variant names:

• chrX-22032898-A-G
• rs149541983
• NM_000444.6:c.-108A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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 Likely 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/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.299
• Publications: 0 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]

PHEX Gene-Disease associations (from GenCC):

• X-linked dominant hypophosphatemic rickets

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 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/Likely_benign. ClinVar VariationId is 368154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000444.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	NM_000444.6	MANE Select	c.-108A>G		5_prime_UTR	Exon 1 of 22	NP_000435.3
	PHEX	NM_001282754.2		c.-108A>G		5_prime_UTR	Exon 1 of 21	NP_001269683.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	ENST00000379374.5	TSL:1 MANE Select	c.-108A>G		5_prime_UTR	Exon 1 of 22	ENSP00000368682.4	P78562
	PHEX	ENST00000684143.1		c.-108A>G		5_prime_UTR	Exon 1 of 11	ENSP00000508264.1	A0A804HLA0
	PHEX	ENST00000475778.2	TSL:5	n.319A>G		non_coding_transcript_exon	Exon 1 of 9

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1331 AN: 111566 Hom.: 22 Cov.: 22

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

African (AFR) AF: 0.0405 AC: 581 AN: 14333

American (AMR) AF: 0.00269 AC: 92 AN: 34179

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15416

East Asian (EAS) AF: 0.00 AC: 0 AN: 27105

South Asian (SAS) AF: 0.000118 AC: 5 AN: 42291

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39726

Middle Eastern (MID) AF: 0.000523 AC: 1 AN: 1913

European-Non Finnish (NFE) AF: 0.0000756 AC: 21 AN: 277900

Other (OTH) AF: 0.00291 AC: 74 AN: 25461

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

African (AFR) AF: 0.0410 AC: 1259 AN: 30670

American (AMR) AF: 0.00460 AC: 48 AN: 10443

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2638

East Asian (EAS) AF: 0.00 AC: 0 AN: 3552

South Asian (SAS) AF: 0.000379 AC: 1 AN: 2641

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000940 AC: 5 AN: 53183

Other (OTH) AF: 0.0138 AC: 21 AN: 1520

Alfa AF: 0.00897 Hom.: 23

Bravo AF: 0.0137

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Familial X-linked hypophosphatemic vitamin D refractory rickets (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.2
DANN	Benign	0.71
PhyloP100		0.30
PromoterAI		0.0041	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs149541983; hg19: chrX-22051016;