chrX-22221603-C-T

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:8
• 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.

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.1769-10C>T		intron	N/A	NP_000435.3
	PHEX	NM_001282754.2		c.1769-10C>T		intron	N/A	NP_001269683.1
	PTCHD1-AS	NR_073010.2		n.1048+5867G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHEX	ENST00000379374.5	TSL:1 MANE Select	c.1769-10C>T		intron	N/A	ENSP00000368682.4	P78562
	PHEX	ENST00000684356.1		c.323-10C>T		intron	N/A	ENSP00000507619.1	A0A804HJR7
	PHEX	ENST00000682888.1		c.323-10C>T		intron	N/A	ENSP00000508003.1	A0A804HKN7

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Familial X-linked hypophosphatemic vitamin D refractory rickets (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
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;