chrX-72676175-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002637.4(PHKA1):c.538-25T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,113,170 control chromosomes in the GnomAD database, including 363 homozygotes. There are 4,473 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 34 hom., 445 hem., cov: 22)

Exomes 𝑓: 0.011 ( 329 hom. 4028 hem. )

Consequence

PHKA1
NM_002637.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.697

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant X-72676175-A-G is Benign according to our data. Variant chrX-72676175-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0982 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKA1	NM_002637.4 link	c.538-25T>C		intron_variant	Intron 5 of 31	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.538-25T>C		intron_variant	Intron 5 of 31	1	NM_002637.4	ENSP00000362643.4		P46020-1

Frequencies

GnomAD3 genomes

AF:

0.0121

AC:

1342

AN:

110821

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00348

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0592

Gnomad ASJ

AF:

0.0125

Gnomad EAS

AF:

0.107

Gnomad SAS

AF:

0.0479

Gnomad FIN

AF:

0.00388

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000699

Gnomad OTH

AF:

0.0203

GnomAD2 exomes

AF:

0.0289

AC:

5261

AN:

182034

AF XY:

0.0274

show subpopulations

Gnomad AFR exome

AF:

0.00282

Gnomad AMR exome

AF:

0.0882

Gnomad ASJ exome

AF:

0.00970

Gnomad EAS exome

AF:

0.111

Gnomad FIN exome

AF:

0.00401

Gnomad NFE exome

AF:

0.000700

Gnomad OTH exome

AF:

0.0251

GnomAD4 exome

AF:

0.0108

AC:

10837

AN:

1002303

Hom.:

329

Cov.:

AF XY:

0.0141

AC XY:

4028

AN XY:

286567

show subpopulations

African (AFR)

AF:

0.00235

AC:

AN:

24671

American (AMR)

AF:

0.0851

AC:

2983

AN:

35061

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

210

AN:

18741

East Asian (EAS)

AF:

0.115

AC:

3426

AN:

29795

South Asian (SAS)

AF:

0.0546

AC:

2824

AN:

51724

European-Finnish (FIN)

AF:

0.00479

AC:

193

AN:

40323

Middle Eastern (MID)

AF:

0.00206

AC:

AN:

3883

European-Non Finnish (NFE)

AF:

0.000481

AC:

363

AN:

755113

Other (OTH)

AF:

0.0180

AC:

772

AN:

42992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

346

693

1039

1386

1732

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

150

300

450

600

750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0121

AC:

1345

AN:

110867

Hom.:

Cov.:

AF XY:

0.0134

AC XY:

445

AN XY:

33105

show subpopulations

African (AFR)

AF:

0.00347

AC:

106

AN:

30539

American (AMR)

AF:

0.0593

AC:

617

AN:

10404

Ashkenazi Jewish (ASJ)

AF:

0.0125

AC:

AN:

2642

East Asian (EAS)

AF:

0.107

AC:

375

AN:

3502

South Asian (SAS)

AF:

0.0473

AC:

119

AN:

2515

European-Finnish (FIN)

AF:

0.00388

AC:

AN:

5929

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.000699

AC:

AN:

52938

Other (OTH)

AF:

0.0234

AC:

AN:

1498

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

133

177

221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00640

Hom.:

Bravo

AF:

0.0177

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jun 29, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 15, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

1.6

(source)

DANN

Benign

0.79

PhyloP100

0.70

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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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