X-72580771-T-A

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.*231A>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 0.00352 in 430,941 control chromosomes in the GnomAD database, including 7 homozygotes. There are 482 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., 103 hem., cov: 23)
  • Exomes 𝑓: 0.0037 (7 hom. 379 hem.)
• Consequence: PHKA1 NM_002637.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.134

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=-0.72).
• BP6: Variant X-72580771-T-A is Benign according to our data. Variant chrX-72580771-T-A is described in ClinVar as [Benign]. Clinvar id is 368641.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00305 (342/112000) while in subpopulation NFE AF= 0.00495 (263/53157). AF 95% confidence interval is 0.00446. There are 0 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 103 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKA1	NM_002637.4	c.*231A>T		3_prime_UTR_variant	32/32	ENST00000373542.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHKA1	ENST00000373542.9	c.*231A>T		3_prime_UTR_variant	32/32	1	NM_002637.4	P4

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 342 AN: 111946 Hom.: 0 Cov.: 23 AF XY: 0.00302 AC XY: 103 AN XY: 34124

Gnomad AFR AF: 0.000746

Gnomad AMI AF: 0.0265

Gnomad AMR AF: 0.00180

Gnomad ASJ AF: 0.000755

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00183

Gnomad MID AF: 0.00422

Gnomad NFE AF: 0.00495

Gnomad OTH AF: 0.00333

GnomAD4 exome AF: 0.00368 AC: 1174 AN: 318941 Hom.: 7 Cov.: 0 AF XY: 0.00356 AC XY: 379 AN XY: 106575

Gnomad4 AFR exome AF: 0.000733

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.000609

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00264

Gnomad4 NFE exome AF: 0.00523

Gnomad4 OTH exome AF: 0.00284

GnomAD4 genome AF: 0.00305 AC: 342 AN: 112000 Hom.: 0 Cov.: 23 AF XY: 0.00301 AC XY: 103 AN XY: 34188

Gnomad4 AFR AF: 0.000745

Gnomad4 AMR AF: 0.00179

Gnomad4 ASJ AF: 0.000755

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00183

Gnomad4 NFE AF: 0.00495

Gnomad4 OTH AF: 0.00329

Alfa AF: 0.00351 Hom.: 18

Bravo AF: 0.00295

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	-0.72
Cadd	Benign	7.0
Dann	Benign	0.90

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: rs374264624; hg19: chrX-71800621;