11-64751590-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005609.4(PYGM):c.1827+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,613,936 control chromosomes in the GnomAD database, including 12,555 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1324 hom., cov: 32)
  • Exomes 𝑓: 0.11 (11231 hom.)
• Consequence: PYGM NM_005609.4 splice_region, intron
• Scores: Splicing: ADA: 0.0004109
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.285

Genes affected

PYGM (HGNC:9726): (glycogen phosphorylase, muscle associated) This gene encodes a muscle enzyme involved in glycogenolysis. Highly similar enzymes encoded by different genes are found in liver and brain. Mutations in this gene are associated with McArdle disease (myophosphorylase deficiency), a glycogen storage disease of muscle. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 11-64751590-T-C is Benign according to our data. Variant chr11-64751590-T-C is described in ClinVar as [Benign]. Clinvar id is 95294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64751590-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGM	NM_005609.4	c.1827+7A>G		splice_region_variant, intron_variant		ENST00000164139.4
PYGM	NM_001164716.1	c.1563+7A>G		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGM	ENST00000164139.4	c.1827+7A>G		splice_region_variant, intron_variant		1	NM_005609.4	P1
PYGM	ENST00000377432.7	c.1563+7A>G		splice_region_variant, intron_variant		2
PYGM	ENST00000462303.1	n.151+7A>G		splice_region_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.112 AC: 16966 AN: 152098 Hom.: 1322 Cov.: 32

Gnomad AFR AF: 0.0695

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.353

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0902

Gnomad OTH AF: 0.112

GnomAD3 exomes AF: 0.144 AC: 36293 AN: 251292 Hom.: 3842 AF XY: 0.139 AC XY: 18873 AN XY: 135802

Gnomad AFR exome AF: 0.0672

Gnomad AMR exome AF: 0.292

Gnomad ASJ exome AF: 0.124

Gnomad EAS exome AF: 0.357

Gnomad SAS exome AF: 0.147

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.0845

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.105 AC: 154152 AN: 1461720 Hom.: 11231 Cov.: 32 AF XY: 0.106 AC XY: 77391 AN XY: 727146

Gnomad4 AFR exome AF: 0.0668

Gnomad4 AMR exome AF: 0.291

Gnomad4 ASJ exome AF: 0.125

Gnomad4 EAS exome AF: 0.379

Gnomad4 SAS exome AF: 0.154

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.0849

Gnomad4 OTH exome AF: 0.110

GnomAD4 genome AF: 0.112 AC: 16993 AN: 152216 Hom.: 1324 Cov.: 32 AF XY: 0.118 AC XY: 8783 AN XY: 74424

Gnomad4 AFR AF: 0.0696

Gnomad4 AMR AF: 0.226

Gnomad4 ASJ AF: 0.130

Gnomad4 EAS AF: 0.353

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.110

Gnomad4 NFE AF: 0.0902

Gnomad4 OTH AF: 0.115

Alfa AF: 0.0934 Hom.: 1068

Bravo AF: 0.120

Asia WGS AF: 0.252 AC: 876 AN: 3478

EpiCase AF: 0.0869

EpiControl AF: 0.0848

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type V Benign:5

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided Benign:2 Other:1

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 28967462) -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 07, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	7.4
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00041
dbscSNV1_RF	Benign	0.24
SpliceAI score (max)		0.050		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: rs532747; hg19: chr11-64519062; COSMIC: COSV51215358; COSMIC: COSV51215358;