X-72599841-A-G

Position:

• chrX-72599841-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002637.4(PHKA1):​c.3072+2150T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 549,092 control chromosomes in the GnomAD database, including 8,874 homozygotes. There are 21,183 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1674 hom., 4368 hem., cov: 22)
  • Exomes 𝑓: 0.11 (7200 hom. 16815 hem.)
• Consequence: PHKA1 NM_002637.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0210

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.3429835E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHKA1	NM_002637.4	c.3072+2150T>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.3072+2150T>C		intron_variant		1	NM_002637.4	ENSP00000362643.4

Frequencies

GnomAD3 genomes AF: 0.133 AC: 14689 AN: 110438 Hom.: 1675 Cov.: 22 AF XY: 0.133 AC XY: 4366 AN XY: 32736

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.0327

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.00921

Gnomad OTH AF: 0.132

GnomAD3 exomes AF: 0.165 AC: 24100 AN: 145859 Hom.: 4251 AF XY: 0.133 AC XY: 6004 AN XY: 45229

Gnomad AFR exome AF: 0.287

Gnomad AMR exome AF: 0.395

Gnomad ASJ exome AF: 0.0245

Gnomad EAS exome AF: 0.679

Gnomad SAS exome AF: 0.194

Gnomad FIN exome AF: 0.0261

Gnomad NFE exome AF: 0.00939

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.110 AC: 48276 AN: 438600 Hom.: 7200 Cov.: 0 AF XY: 0.106 AC XY: 16815 AN XY: 158758

Gnomad4 AFR exome AF: 0.280

Gnomad4 AMR exome AF: 0.383

Gnomad4 ASJ exome AF: 0.0283

Gnomad4 EAS exome AF: 0.688

Gnomad4 SAS exome AF: 0.196

Gnomad4 FIN exome AF: 0.0269

Gnomad4 NFE exome AF: 0.00984

Gnomad4 OTH exome AF: 0.0984

GnomAD4 genome AF: 0.133 AC: 14696 AN: 110492 Hom.: 1674 Cov.: 22 AF XY: 0.133 AC XY: 4368 AN XY: 32800

Gnomad4 AFR AF: 0.276

Gnomad4 AMR AF: 0.249

Gnomad4 ASJ AF: 0.0327

Gnomad4 EAS AF: 0.672

Gnomad4 SAS AF: 0.213

Gnomad4 FIN AF: 0.0221

Gnomad4 NFE AF: 0.00921

Gnomad4 OTH AF: 0.134

Alfa AF: 0.0682 Hom.: 980

Bravo AF: 0.169

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00935 AC: 27

ESP6500AA AF: 0.287 AC: 407

ESP6500EA AF: 0.00967 AC: 30

ExAC AF: 0.146 AC: 16573

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.8
DANN	Benign	0.24
DEOGEN2	Benign	0.0058	T;T
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.52	T;T
MetaRNN	Benign	0.0000093	T;T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	0.010	N;N
REVEL	Benign	0.073
Sift	Benign	0.57	T;T
Sift4G	Benign	0.63	T;T
Vest4		0.098
ClinPred		0.0057	T
GERP RS		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs7054230; hg19: chrX-71819691;