11-64751590-T-C

Variant names:

• chr11-64751590-T-C
• rs532747
• NM_005609.4:c.1827+7A>G

Variant summary

Our verdict is Benign. The variant received -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:10 O:1
• Conservation: PhyloP100: -0.285
• Publications: 16 publications found

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]

PYGM Gene-Disease associations (from GenCC):

• glycogen storage disease V

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 95294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005609.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGM	NM_005609.4	MANE Select	c.1827+7A>G		splice_region intron	N/A	NP_005600.1
	PYGM	NM_001164716.1		c.1563+7A>G		splice_region intron	N/A	NP_001158188.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGM	ENST00000164139.4	TSL:1 MANE Select	c.1827+7A>G		splice_region intron	N/A	ENSP00000164139.3
	PYGM	ENST00000967737.1		c.1926+7A>G		splice_region intron	N/A	ENSP00000637796.1
	PYGM	ENST00000938870.1		c.1743+7A>G		splice_region intron	N/A	ENSP00000608929.1

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

GnomAD2 exomes AF: 0.144 AC: 36293 AN: 251292 AF XY: 0.139

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 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

African (AFR) AF: 0.0668 AC: 2236 AN: 33480

American (AMR) AF: 0.291 AC: 12993 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 3255 AN: 26136

East Asian (EAS) AF: 0.379 AC: 15039 AN: 39700

South Asian (SAS) AF: 0.154 AC: 13297 AN: 86258

European-Finnish (FIN) AF: 0.110 AC: 5883 AN: 53378

Middle Eastern (MID) AF: 0.0751 AC: 433 AN: 5768

European-Non Finnish (NFE) AF: 0.0849 AC: 94359 AN: 1111896

Other (OTH) AF: 0.110 AC: 6657 AN: 60380

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

African (AFR) AF: 0.0696 AC: 2893 AN: 41548

American (AMR) AF: 0.226 AC: 3458 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 451 AN: 3472

East Asian (EAS) AF: 0.353 AC: 1823 AN: 5166

South Asian (SAS) AF: 0.163 AC: 784 AN: 4824

European-Finnish (FIN) AF: 0.110 AC: 1163 AN: 10612

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0902 AC: 6137 AN: 68004

Other (OTH) AF: 0.115 AC: 242 AN: 2106

Alfa AF: 0.0959 Hom.: 1358

Bravo AF: 0.120

Asia WGS AF: 0.252 AC: 876 AN: 3478

EpiCase AF: 0.0869

EpiControl AF: 0.0848

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Glycogen storage disease, type V (5)
-	-	3	not provided (4)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.4
DANN	Benign	0.64
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs532747; hg19: chr11-64519062; COSMIC: COSV51215358; COSMIC: COSV51215358;