X-72580198-G-A

Variant names:

• chrX-72580198-G-A
• rs144538626
• NM_002637.4:c.*804C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002637.4(PHKA1):​c.*804C>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 0.00246 in 111,864 control chromosomes in the GnomAD database, including 1 homozygotes. There are 75 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., 75 hem., cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PHKA1 NM_002637.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.752
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-72580198-G-A is Benign according to our data. Variant chrX-72580198-G-A is described in ClinVar as [Benign]. Clinvar id is 912526.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00246 (275/111864) while in subpopulation AMR AF = 0.00663 (70/10564). AF 95% confidence interval is 0.00538. There are 1 homozygotes in GnomAd4. There are 75 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 75 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKA1	NM_002637.4	c.*804C>T		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.*804C>T		3_prime_UTR_variant	Exon 32 of 32	1	NM_002637.4	ENSP00000362643.4
PHKA1	ENST00000339490.7	c.*804C>T		3_prime_UTR_variant	Exon 31 of 31	1		ENSP00000342469.3
PHKA1	ENST00000541944.5	c.*804C>T		3_prime_UTR_variant	Exon 30 of 30	1		ENSP00000441251.1
PHKA1	ENST00000373545.7	c.*804C>T		3_prime_UTR_variant	Exon 32 of 32	5		ENSP00000362646.3

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 275 AN: 111809 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.00465

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00663

Gnomad ASJ AF: 0.000378

Gnomad EAS AF: 0.000558

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00840

Gnomad NFE AF: 0.000960

Gnomad OTH AF: 0.00397

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 20 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 6

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: 18

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.00246 AC: 275 AN: 111864 Hom.: 1 Cov.: 23 AF XY: 0.00220 AC XY: 75 AN XY: 34034

African (AFR) AF: 0.00464 AC: 143 AN: 30839

American (AMR) AF: 0.00663 AC: 70 AN: 10564

Ashkenazi Jewish (ASJ) AF: 0.000378 AC: 1 AN: 2645

East Asian (EAS) AF: 0.000560 AC: 2 AN: 3574

South Asian (SAS) AF: 0.00 AC: 0 AN: 2634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6026

Middle Eastern (MID) AF: 0.00917 AC: 2 AN: 218

European-Non Finnish (NFE) AF: 0.000960 AC: 51 AN: 53146

Other (OTH) AF: 0.00392 AC: 6 AN: 1532

Alfa AF: 0.00157 Hom.: 6

Bravo AF: 0.00311

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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	-0.85
CADD	Benign	0.11
DANN	Benign	0.68
PhyloP100		-0.75
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: rs144538626; hg19: chrX-71800048;