X-72579737-T-TACAC

Variant names:

• chrX-72579737-T-TACAC
• rs111688568
• NM_002637.4:c.*1261_*1264dupGTGT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_002637.4(PHKA1):​c.*1261_*1264dupGTGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., 87 hem., cov: 19)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PHKA1 NM_002637.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62
• 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00326 (346/106240) while in subpopulation AFR AF = 0.0109 (318/29085). AF 95% confidence interval is 0.00994. There are 1 homozygotes in GnomAd4. There are 87 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd4 at 87 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKA1	NM_002637.4	c.*1261_*1264dupGTGT		3_prime_UTR_variant	Exon 32 of 32	ENST00000373542.9	NP_002628.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHKA1	ENST00000373542.9	c.*1261_*1264dupGTGT		3_prime_UTR_variant	Exon 32 of 32	1	NM_002637.4	ENSP00000362643.4
PHKA1	ENST00000339490.7	c.*1261_*1264dupGTGT		3_prime_UTR_variant	Exon 31 of 31	1		ENSP00000342469.3
PHKA1	ENST00000541944.5	c.*1261_*1264dupGTGT		3_prime_UTR_variant	Exon 30 of 30	1		ENSP00000441251.1
PHKA1	ENST00000373545.7	c.*1261_*1264dupGTGT		3_prime_UTR_variant	Exon 32 of 32	5		ENSP00000362646.3

Frequencies

GnomAD3 genomes AF: 0.00324 AC: 344 AN: 106218 Hom.: 1 Cov.: 19

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000288

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00431

Gnomad NFE AF: 0.0000975

Gnomad OTH AF: 0.00211

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 36 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 22

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 33

Other (OTH) AF: 0.00 AC: 0 AN: 3

GnomAD4 genome AF: 0.00326 AC: 346 AN: 106240 Hom.: 1 Cov.: 19 AF XY: 0.00289 AC XY: 87 AN XY: 30148

African (AFR) AF: 0.0109 AC: 318 AN: 29085

American (AMR) AF: 0.00183 AC: 18 AN: 9850

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2534

East Asian (EAS) AF: 0.000289 AC: 1 AN: 3463

South Asian (SAS) AF: 0.00 AC: 0 AN: 2450

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5265

Middle Eastern (MID) AF: 0.00469 AC: 1 AN: 213

European-Non Finnish (NFE) AF: 0.0000975 AC: 5 AN: 51272

Other (OTH) AF: 0.00208 AC: 3 AN: 1441

Alfa AF: 0.00 Hom.: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glycogen phosphorylase kinase deficiency Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs111688568; hg19: chrX-71799587;