X-72676175-A-G

Variant names:

• chrX-72676175-A-G
• rs149014464
• NM_002637.4:c.538-25T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.697
• Publications: 0 publications found

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)

ACMG classification

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	c.538-25T>C		intron_variant	Intron 5 of 31	ENST00000373542.9	NP_002628.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHKA1	ENST00000373542.9	c.538-25T>C		intron_variant	Intron 5 of 31	1	NM_002637.4	ENSP00000362643.4

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1342 AN: 110821 Hom.: 34 Cov.: 22

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

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.: 21 AF XY: 0.0141 AC XY: 4028 AN XY: 286567

African (AFR) AF: 0.00235 AC: 58 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: 8 AN: 3883

European-Non Finnish (NFE) AF: 0.000481 AC: 363 AN: 755113

Other (OTH) AF: 0.0180 AC: 772 AN: 42992

GnomAD4 genome AF: 0.0121 AC: 1345 AN: 110867 Hom.: 34 Cov.: 22 AF XY: 0.0134 AC XY: 445 AN XY: 33105

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: 33 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: 23 AN: 5929

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.000699 AC: 37 AN: 52938

Other (OTH) AF: 0.0234 AC: 35 AN: 1498

Alfa AF: 0.00640 Hom.: 47

Bravo AF: 0.0177

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

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
DANN	Benign	0.79
PhyloP100		0.70
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs149014464; hg19: chrX-71896025;