X-72579737-TACACACACACACAC-TACACACACAC

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_002637.4(PHKA1):​c.*1261_*1264delGTGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., 46 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: Not reported in ClinVar
• 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00144 (153/106241) while in subpopulation NFE AF = 0.00185 (95/51268). AF 95% confidence interval is 0.00155. There are 0 homozygotes in GnomAd4. There are 46 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 46 XL,AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 153 AN: 106217 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00173

Gnomad ASJ AF: 0.00197

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00551

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00185

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 36 Hom.: 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: 0.00144 AC: 153 AN: 106241 Hom.: 0 Cov.: 19 AF XY: 0.00153 AC XY: 46 AN XY: 30153

African (AFR) AF: 0.000241 AC: 7 AN: 29095

American (AMR) AF: 0.00173 AC: 17 AN: 9849

Ashkenazi Jewish (ASJ) AF: 0.00197 AC: 5 AN: 2534

East Asian (EAS) AF: 0.00 AC: 0 AN: 3463

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

European-Finnish (FIN) AF: 0.00551 AC: 29 AN: 5261

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 213

European-Non Finnish (NFE) AF: 0.00185 AC: 95 AN: 51268

Other (OTH) AF: 0.00 AC: 0 AN: 1441

Alfa AF: 0.00174 Hom.: 7

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

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

Other links and lift over

dbSNP: rs111688568; hg19: chrX-71799587;