rs782365144

chrX-72582453-A-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3 BS1_Supporting BS2

The NM_002637.4(PHKA1):c.3443T>G(p.Ile1148Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,205,241 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I1148I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000016 (0 hom. 7 hem.)
• Consequence: PHKA1 NM_002637.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.22

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 Likely_benign. Variant got -4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000134 (15/111819) while in subpopulation AFR AF= 0.000488 (15/30751). AF 95% confidence interval is 0.0003. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKA1	NM_002637.4	c.3443T>G	p.Ile1148Ser	missense_variant	31/32	ENST00000373542.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHKA1	ENST00000373542.9	c.3443T>G	p.Ile1148Ser	missense_variant	31/32	1	NM_002637.4	P4

Frequencies

GnomAD3 genomes AF: 0.000134 AC: 15 AN: 111819 Hom.: 0 Cov.: 22 AF XY: 0.0000589 AC XY: 2 AN XY: 33975

Gnomad AFR AF: 0.000488

Gnomad AMI AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000491 AC: 9 AN: 183394 Hom.: 0 AF XY: 0.0000737 AC XY: 5 AN XY: 67840

Gnomad AFR exome AF: 0.000456

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000155 AC: 17 AN: 1093422 Hom.: 0 Cov.: 29 AF XY: 0.0000195 AC XY: 7 AN XY: 358902

Gnomad4 AFR exome AF: 0.000456

Gnomad4 AMR exome AF: 0.0000852

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000435

GnomAD4 genome AF: 0.000134 AC: 15 AN: 111819 Hom.: 0 Cov.: 22 AF XY: 0.0000589 AC XY: 2 AN XY: 33975

Gnomad4 AFR AF: 0.000488

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000140

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease IXd Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 12, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1148 of the PHKA1 protein (p.Ile1148Ser). This variant is present in population databases (rs782365144, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of PHKA1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 432361). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 22, 2018

A variant of uncertain significance has been identified in the PHKA1 gene. The I1148S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I1148S variant is observed in 2/8502 (0.02%) alleles from individuals of African background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The I1148S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in Human Gene Mutation Database in association with PHKA1-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D;T;.;.;T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.4	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.1	D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D
Polyphen		0.99	D;P;P;.;.
Vest4		0.78
MVP		0.96
MPC		0.65
ClinPred		0.41	T
GERP RS		5.2
Varity_R		0.90
gMVP		0.74

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: rs782365144; hg19: chrX-71802303;