chrX-72695716-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_002637.4(PHKA1):​c.446C>T​(p.Thr149Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. T149A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)
Exomes 𝑓: 0.0000036 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control

Consequence

PHKA1
NM_002637.4 missense

Scores

10
5
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.98
Variant links:
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-AS1 (HGNC:40446): (PHKA1 antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.771

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PHKA1NM_002637.4 linkuse as main transcriptc.446C>T p.Thr149Ile missense_variant 4/32 ENST00000373542.9
PHKA1-AS1NR_110391.1 linkuse as main transcriptn.55-1443G>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PHKA1ENST00000373542.9 linkuse as main transcriptc.446C>T p.Thr149Ile missense_variant 4/321 NM_002637.4 P4P46020-1
PHKA1-AS1ENST00000420998.1 linkuse as main transcriptn.54-1443G>A intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000365
AC:
4
AN:
1096309
Hom.:
0
Cov.:
29
AF XY:
0.00
AC XY:
0
AN XY:
362569
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000475
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Glycogen storage disease IXd Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 09, 2022In 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with PHKA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 149 of the PHKA1 protein (p.Thr149Ile). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.59
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.43
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.75
D;D;.;.;D
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D;D;D;D
M_CAP
Pathogenic
0.82
D
MetaRNN
Pathogenic
0.77
D;D;D;D;D
MetaSVM
Uncertain
0.41
D
MutationAssessor
Benign
1.9
L;.;L;L;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-5.6
D;D;D;D;D
REVEL
Pathogenic
0.88
Sift
Pathogenic
0.0
D;D;D;D;D
Sift4G
Uncertain
0.021
D;D;D;D;D
Polyphen
1.0
D;.;D;.;.
Vest4
0.53
MutPred
0.73
Loss of glycosylation at S151 (P = 0.1173);Loss of glycosylation at S151 (P = 0.1173);Loss of glycosylation at S151 (P = 0.1173);Loss of glycosylation at S151 (P = 0.1173);Loss of glycosylation at S151 (P = 0.1173);
MVP
0.92
MPC
1.0
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.90
gMVP
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-71915566; API