chrX-72695773-C-T

Position:

chrX-72695773-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 10P and 4B. PVS1PP5_ModerateBS2

The NM_002637.4(PHKA1):c.389G>A(p.Trp130Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,204,096 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000016 ( 0 hom. 6 hem. )

Consequence

PHKA1
NM_002637.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.79

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 links:

PHKA1-AS1 (HGNC:40446): (PHKA1 antisense RNA 1)

PHKA1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant X-72695773-C-T is Pathogenic according to our data. Variant chrX-72695773-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3010358.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKA1	NM_002637.4 linkuse as main transcript	c.389G>A	p.Trp130Ter	stop_gained	4/32	ENST00000373542.9
PHKA1-AS1	NR_110391.1 linkuse as main transcript	n.55-1386C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHKA1	ENST00000373542.9 linkuse as main transcript	c.389G>A	p.Trp130Ter	stop_gained	4/32	1	NM_002637.4	P4	P46020-1
PHKA1-AS1	ENST00000420998.1 linkuse as main transcript	n.54-1386C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00000901

AC:

AN:

110939

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33129

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183337

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67823

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000156

AC:

AN:

1093157

Hom.:

Cov.:

AF XY:

0.0000167

AC XY:

AN XY:

358907

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:

0.0000203

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000901

AC:

AN:

110939

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33129

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000189

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Glycogen storage disease IXd

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 11, 2023

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with PHKA1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Trp130*) in the PHKA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PHKA1 are known to be pathogenic (PMID: 9731190, 15637709). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.71

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

FATHMM_MKL

Uncertain

0.96

MutationTaster

Benign

1.0

A;A;A;A;A

Vest4

0.48

GERP RS

3.8

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over