rs374264624

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_002637.4(PHKA1):c.*231A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00352 in 430,941 control chromosomes in the GnomAD database, including 7 homozygotes. There are 482 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0031 ( 0 hom., 103 hem., cov: 23)

Exomes 𝑓: 0.0037 ( 7 hom. 379 hem. )

Consequence

PHKA1
NM_002637.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.134

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

glycogen storage disease IXd
Inheritance: XL, AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

PHKA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant X-72580771-T-A is Benign according to our data. Variant chrX-72580771-T-A is described in ClinVar as [Benign]. Clinvar id is 368641.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00305 (342/112000) while in subpopulation NFE AF = 0.00495 (263/53157). AF 95% confidence interval is 0.00446. There are 0 homozygotes in GnomAd4. There are 103 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 103 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKA1	NM_002637.4 link	c.*231A>T		3_prime_UTR_variant	Exon 32 of 32	ENST00000373542.9	NP_002628.2	P46020-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHKA1	ENST00000373542.9 link	c.*231A>T		3_prime_UTR_variant	Exon 32 of 32	1	NM_002637.4	ENSP00000362643.4		P46020-1

Frequencies

GnomAD3 genomes

AF:

0.00306

AC:

342

AN:

111946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000746

Gnomad AMI

AF:

0.0265

Gnomad AMR

AF:

0.00180

Gnomad ASJ

AF:

0.000755

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00183

Gnomad MID

AF:

0.00422

Gnomad NFE

AF:

0.00495

Gnomad OTH

AF:

0.00333

GnomAD4 exome

AF:

0.00368

AC:

1174

AN:

318941

Hom.:

Cov.:

AF XY:

0.00356

AC XY:

379

AN XY:

106575

show subpopulations

African (AFR)

AF:

0.000733

AC:

AN:

9550

American (AMR)

AF:

0.00119

AC:

AN:

14312

Ashkenazi Jewish (ASJ)

AF:

0.000609

AC:

AN:

9846

East Asian (EAS)

AF:

0.00

AC:

AN:

22693

South Asian (SAS)

AF:

0.000197

AC:

AN:

25438

European-Finnish (FIN)

AF:

0.00264

AC:

AN:

21975

Middle Eastern (MID)

AF:

0.00659

AC:

AN:

1365

European-Non Finnish (NFE)

AF:

0.00523

AC:

1017

AN:

194420

Other (OTH)

AF:

0.00284

AC:

AN:

19342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

137

183

229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00305

AC:

342

AN:

112000

Hom.:

Cov.:

AF XY:

0.00301

AC XY:

103

AN XY:

34188

show subpopulations

African (AFR)

AF:

0.000745

AC:

AN:

30881

American (AMR)

AF:

0.00179

AC:

AN:

10589

Ashkenazi Jewish (ASJ)

AF:

0.000755

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3563

South Asian (SAS)

AF:

0.00

AC:

AN:

2721

European-Finnish (FIN)

AF:

0.00183

AC:

AN:

6027

Middle Eastern (MID)

AF:

0.00463

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00495

AC:

263

AN:

53157

Other (OTH)

AF:

0.00329

AC:

AN:

1519

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00351

Hom.:

Bravo

AF:

0.00295

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Glycogen storage disease IXd

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

7.0

(source)

DANN

Benign

0.90

PhyloP100

-0.13

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs374264624

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over