rs138066694

Positions:

chrX-72695733-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_002637.4(PHKA1):c.429C>T(p.Leu143=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0353 in 1,207,676 control chromosomes in the GnomAD database, including 643 homozygotes. There are 13,439 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 52 hom., 812 hem., cov: 22)

Exomes 𝑓: 0.036 ( 591 hom. 12627 hem. )

Consequence

PHKA1
NM_002637.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.717

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 Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant X-72695733-G-A is Benign according to our data. Variant chrX-72695733-G-A is described in ClinVar as [Benign]. Clinvar id is 258785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-72695733-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.717 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0271 (3019/111244) while in subpopulation NFE AF= 0.0423 (2242/53031). AF 95% confidence interval is 0.0408. There are 52 homozygotes in gnomad4. There are 812 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 52 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKA1	NM_002637.4 linkuse as main transcript	c.429C>T	p.Leu143=	synonymous_variant	4/32	ENST00000373542.9
PHKA1-AS1	NR_110391.1 linkuse as main transcript	n.55-1426G>A		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.429C>T	p.Leu143=	synonymous_variant	4/32	1	NM_002637.4	P4	P46020-1
PHKA1-AS1	ENST00000420998.1 linkuse as main transcript	n.54-1426G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0272

AC:

3020

AN:

111194

Hom.:

Cov.:

AF XY:

0.0244

AC XY:

813

AN XY:

33376

show subpopulations

Gnomad AFR

AF:

0.00533

Gnomad AMI

AF:

0.00145

Gnomad AMR

AF:

0.0283

Gnomad ASJ

AF:

0.0461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00926

Gnomad FIN

AF:

0.0187

Gnomad MID

AF:

0.0295

Gnomad NFE

AF:

0.0423

Gnomad OTH

AF:

0.0366

GnomAD3 exomes

AF:

0.0254

AC:

4649

AN:

183269

Hom.:

AF XY:

0.0249

AC XY:

1689

AN XY:

67753

show subpopulations

Gnomad AFR exome

AF:

0.00410

Gnomad AMR exome

AF:

0.0175

Gnomad ASJ exome

AF:

0.0429

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00771

Gnomad FIN exome

AF:

0.0172

Gnomad NFE exome

AF:

0.0396

Gnomad OTH exome

AF:

0.0300

GnomAD4 exome

AF:

0.0361

AC:

39596

AN:

1096432

Hom.:

591

Cov.:

AF XY:

0.0348

AC XY:

12627

AN XY:

362618

show subpopulations

Gnomad4 AFR exome

AF:

0.00455

Gnomad4 AMR exome

AF:

0.0183

Gnomad4 ASJ exome

AF:

0.0429

Gnomad4 EAS exome

AF:

0.0000662

Gnomad4 SAS exome

AF:

0.00864

Gnomad4 FIN exome

AF:

0.0189

Gnomad4 NFE exome

AF:

0.0418

Gnomad4 OTH exome

AF:

0.0321

GnomAD4 genome

AF:

0.0271

AC:

3019

AN:

111244

Hom.:

Cov.:

AF XY:

0.0243

AC XY:

812

AN XY:

33436

show subpopulations

Gnomad4 AFR

AF:

0.00532

Gnomad4 AMR

AF:

0.0283

Gnomad4 ASJ

AF:

0.0461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00929

Gnomad4 FIN

AF:

0.0187

Gnomad4 NFE

AF:

0.0423

Gnomad4 OTH

AF:

0.0362

Alfa

AF:

0.0330

Hom.:

239

Bravo

AF:

0.0269

EpiCase

AF:

0.0448

EpiControl

AF:

0.0428

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Glycogen storage disease IXd

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

May 17, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

5.3

DANN

Benign

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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