rs782344973

Variant names:

• chrX-72601995-C-T
• rs782344973
• NM_002637.4:c.3068G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_002637.4(PHKA1):​c.3068G>A​(p.Ser1023Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000894 in 111,881 control chromosomes in the GnomAD database, including 4 homozygotes. There are 36 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1023G) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.00089 (4 hom., 36 hem., cov: 22)
• Consequence: PHKA1 NM_002637.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.801
• Publications: 0 publications found

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]

PHKA1 Gene-Disease associations (from GenCC):

• glycogen storage disease IXd

  Inheritance: XL, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 4 XL,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002637.4. 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
	PHKA1	NM_002637.4	MANE Select	c.3068G>A	p.Ser1023Asn	missense	Exon 28 of 32	NP_002628.2	P46020-1
	PHKA1	NM_001431068.1		c.3068G>A	p.Ser1023Asn	missense	Exon 28 of 33	NP_001417997.1	A6NMN0
	PHKA1	NM_001122670.2		c.3033+163G>A		intron	N/A	NP_001116142.1	P46020-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHKA1	ENST00000373542.9	TSL:1 MANE Select	c.3068G>A	p.Ser1023Asn	missense	Exon 28 of 32	ENSP00000362643.4	P46020-1
	PHKA1	ENST00000339490.7	TSL:1	c.3033+163G>A		intron	N/A	ENSP00000342469.3	P46020-2
	PHKA1	ENST00000541944.5	TSL:1	c.2856+163G>A		intron	N/A	ENSP00000441251.1	P46020-3

Frequencies

GnomAD3 genomes AF: 0.000894 AC: 100 AN: 111881 Hom.: 4 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.143

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: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000114 AC: 2 AN: 175999 AF XY: 0.0000163

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000257

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 27

GnomAD4 genome AF: 0.000894 AC: 100 AN: 111881 Hom.: 4 Cov.: 22 AF XY: 0.00106 AC XY: 36 AN XY: 34067

African (AFR) AF: 0.00 AC: 0 AN: 30815

American (AMR) AF: 0.00 AC: 0 AN: 10538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3540

South Asian (SAS) AF: 0.00 AC: 0 AN: 2696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53128

Other (OTH) AF: 0.00 AC: 0 AN: 1499

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00130

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Glycogen storage disease IXd (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.20	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0031	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.80
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.23
Sift	Benign	0.49	T
Sift4G	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.33		Loss of phosphorylation at S1023 (P = 0.0107)
MVP		0.71
MPC		0.28
ClinPred		0.12	T
GERP RS		5.4
Varity_R		0.12
gMVP		0.25
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.30		Position offset: 34

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs782344973; hg19: chrX-71821845;