rs149014464

Positions:

• chrX-72676175-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002637.4(PHKA1):​c.538-25T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,113,170 control chromosomes in the GnomAD database, including 363 homozygotes. There are 4,473 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 (34 hom., 445 hem., cov: 22)
  • Exomes 𝑓: 0.011 (329 hom. 4028 hem.)
• Consequence: PHKA1 NM_002637.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.697

Genes affected

PHKA1 (HGNC:8925): (phosphorylase kinase regulatory subunit alpha 1) Phosphorylase kinase is a polymer of 16 subunits, four each of alpha, beta, gamma and delta. The alpha subunit includes the skeletal muscle and hepatic isoforms, and the skeletal muscle isoform is encoded by this gene. The beta subunit is the same in both the muscle and hepatic isoforms, and encoded by one gene. The gamma subunit also includes the skeletal muscle and hepatic isoforms, which are encoded by two different genes. The delta subunit is a calmodulin and can be encoded by three different genes. The gamma subunits contain the active site of the enzyme, whereas the alpha and beta subunits have regulatory functions controlled by phosphorylation. The delta subunit mediates the dependence of the enzyme on calcium concentration. Mutations in this gene cause glycogen storage disease type 9D, also known as X-linked muscle glycogenosis. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene. A pseudogene has been found on chromosome 1.[provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant X-72676175-A-G is Benign according to our data. Variant chrX-72676175-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 258786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0982 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHKA1	NM_002637.4	c.538-25T>C		intron_variant		ENST00000373542.9	NP_002628.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHKA1	ENST00000373542.9	c.538-25T>C		intron_variant		1	NM_002637.4	ENSP00000362643.4

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1342 AN: 110821 Hom.: 34 Cov.: 22 AF XY: 0.0136 AC XY: 448 AN XY: 33049

Gnomad AFR AF: 0.00348

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0592

Gnomad ASJ AF: 0.0125

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.0479

Gnomad FIN AF: 0.00388

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000699

Gnomad OTH AF: 0.0203

GnomAD3 exomes AF: 0.0289 AC: 5261 AN: 182034 Hom.: 177 AF XY: 0.0274 AC XY: 1826 AN XY: 66592

Gnomad AFR exome AF: 0.00282

Gnomad AMR exome AF: 0.0882

Gnomad ASJ exome AF: 0.00970

Gnomad EAS exome AF: 0.111

Gnomad SAS exome AF: 0.0525

Gnomad FIN exome AF: 0.00401

Gnomad NFE exome AF: 0.000700

Gnomad OTH exome AF: 0.0251

GnomAD4 exome AF: 0.0108 AC: 10837 AN: 1002303 Hom.: 329 Cov.: 21 AF XY: 0.0141 AC XY: 4028 AN XY: 286567

Gnomad4 AFR exome AF: 0.00235

Gnomad4 AMR exome AF: 0.0851

Gnomad4 ASJ exome AF: 0.0112

Gnomad4 EAS exome AF: 0.115

Gnomad4 SAS exome AF: 0.0546

Gnomad4 FIN exome AF: 0.00479

Gnomad4 NFE exome AF: 0.000481

Gnomad4 OTH exome AF: 0.0180

GnomAD4 genome AF: 0.0121 AC: 1345 AN: 110867 Hom.: 34 Cov.: 22 AF XY: 0.0134 AC XY: 445 AN XY: 33105

Gnomad4 AFR AF: 0.00347

Gnomad4 AMR AF: 0.0593

Gnomad4 ASJ AF: 0.0125

Gnomad4 EAS AF: 0.107

Gnomad4 SAS AF: 0.0473

Gnomad4 FIN AF: 0.00388

Gnomad4 NFE AF: 0.000699

Gnomad4 OTH AF: 0.0234

Alfa AF: 0.00640 Hom.: 47

Bravo AF: 0.0177

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.6
DANN	Benign	0.79

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: rs149014464; hg19: chrX-71896025;