X-72579627-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002637.4(PHKA1):c.*1375A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00323 in 111,283 control chromosomes in the GnomAD database, including 1 homozygotes. There are 103 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., 103 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: -1.33

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant X-72579627-T-C is Benign according to our data. Variant chrX-72579627-T-C is described in ClinVar as [Benign]. Clinvar id is 912524.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00323 (359/111283) while in subpopulation AFR AF= 0.0113 (347/30596). AF 95% confidence interval is 0.0104. There are 1 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 102 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKA1	NM_002637.4	c.*1375A>G		3_prime_UTR_variant	32/32	ENST00000373542.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHKA1	ENST00000373542.9	c.*1375A>G		3_prime_UTR_variant	32/32	1	NM_002637.4	P4
PHKA1	ENST00000339490.7	c.*1375A>G		3_prime_UTR_variant	31/31	1
PHKA1	ENST00000541944.5	c.*1375A>G		3_prime_UTR_variant	30/30	1
PHKA1	ENST00000373545.7	c.*1375A>G		3_prime_UTR_variant	32/32	5

Frequencies

GnomAD3 genomes AF: 0.00321 AC: 357 AN: 111233 Hom.: 1 Cov.: 23 AF XY: 0.00305 AC XY: 102 AN XY: 33459

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000480

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.0000377

Gnomad OTH AF: 0.00201

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 7 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 5

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00323 AC: 359 AN: 111283 Hom.: 1 Cov.: 23 AF XY: 0.00307 AC XY: 103 AN XY: 33519

Gnomad4 AFR AF: 0.0113

Gnomad4 AMR AF: 0.000479

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000377

Gnomad4 OTH AF: 0.00198

Alfa AF: 0.000357 Hom.: 2

Bravo AF: 0.00399

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glycogen storage disease IXd Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.91
Cadd	Benign	0.023
Dann	Benign	0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs142925152; hg19: chrX-71799477;