X-72581005-T-A

Variant names:

• chrX-72581005-T-A
• rs782257959
• NM_002637.4:c.3669A>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_002637.4(PHKA1):​c.3669A>T​(p.Gln1223His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000365 in 1,096,822 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q1223Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000036 (0 hom. 2 hem.)
• Consequence: PHKA1 NM_002637.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.628
• 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 -1 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 2 XL,AR geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.3669A>T	p.Gln1223His	missense	Exon 32 of 32	NP_002628.2	P46020-1
	PHKA1	NM_001431068.1		c.3720A>T	p.Gln1240His	missense	Exon 33 of 33	NP_001417997.1	A6NMN0
	PHKA1	NM_001122670.2		c.3630A>T	p.Gln1210His	missense	Exon 31 of 31	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.3669A>T	p.Gln1223His	missense	Exon 32 of 32	ENSP00000362643.4	P46020-1
	PHKA1	ENST00000339490.7	TSL:1	c.3630A>T	p.Gln1210His	missense	Exon 31 of 31	ENSP00000342469.3	P46020-2
	PHKA1	ENST00000541944.5	TSL:1	c.3453A>T	p.Gln1151His	missense	Exon 30 of 30	ENSP00000441251.1	P46020-3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000365 AC: 4 AN: 1096822 Hom.: 0 Cov.: 29 AF XY: 0.00000552 AC XY: 2 AN XY: 362230

African (AFR) AF: 0.00 AC: 0 AN: 26383

American (AMR) AF: 0.00 AC: 0 AN: 35157

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19368

East Asian (EAS) AF: 0.00 AC: 0 AN: 30186

South Asian (SAS) AF: 0.00 AC: 0 AN: 53927

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40495

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.00000476 AC: 4 AN: 841123

Other (OTH) AF: 0.00 AC: 0 AN: 46055

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.63
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.50
MutPred		0.40		Gain of glycosylation at S1218 (P = 0.0903)
MVP		0.88
MPC		0.72
ClinPred		0.98	D
GERP RS		-1.7
Varity_R		0.73
gMVP		0.44
Mutation Taster		=80/20	polymorphism

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: rs782257959; hg19: chrX-71800855;