rs477549

Variant names:

• chr11-64759608-T-C
• rs477549
• NM_005609.4:c.243+48A>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.243+48A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,607,264 control chromosomes in the GnomAD database, including 20,527 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4331 hom., cov: 32)
  • Exomes 𝑓: 0.13 (16196 hom.)
• Consequence: PYGM NM_005609.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.83
• Publications: 21 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: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-64759608-T-C is Benign according to our data. Variant chr11-64759608-T-C is described in ClinVar as Benign. ClinVar VariationId is 259835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.361 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.243+48A>G		intron	N/A	NP_005600.1	P11217-1
	PYGM	NM_001164716.1		c.243+48A>G		intron	N/A	NP_001158188.1	P11217-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGM	ENST00000164139.4	TSL:1 MANE Select	c.243+48A>G		intron	N/A	ENSP00000164139.3	P11217-1
	PYGM	ENST00000967737.1		c.243+48A>G		intron	N/A	ENSP00000637796.1
	PYGM	ENST00000938870.1		c.243+48A>G		intron	N/A	ENSP00000608929.1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31149 AN: 151936 Hom.: 4323 Cov.: 32

Gnomad AFR AF: 0.366

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.271

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0996

Gnomad OTH AF: 0.190

GnomAD2 exomes AF: 0.183 AC: 44783 AN: 244904 AF XY: 0.173

Gnomad AFR exome AF: 0.372

Gnomad AMR exome AF: 0.315

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.379

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.0952

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.125 AC: 182290 AN: 1455210 Hom.: 16196 Cov.: 32 AF XY: 0.126 AC XY: 91204 AN XY: 723876

African (AFR) AF: 0.369 AC: 12324 AN: 33398

American (AMR) AF: 0.316 AC: 14101 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 3839 AN: 26094

East Asian (EAS) AF: 0.407 AC: 16123 AN: 39654

South Asian (SAS) AF: 0.204 AC: 17565 AN: 86172

European-Finnish (FIN) AF: 0.110 AC: 5384 AN: 48912

Middle Eastern (MID) AF: 0.117 AC: 596 AN: 5112

European-Non Finnish (NFE) AF: 0.0935 AC: 103853 AN: 1111024

Other (OTH) AF: 0.141 AC: 8505 AN: 60184

GnomAD4 genome AF: 0.205 AC: 31198 AN: 152054 Hom.: 4331 Cov.: 32 AF XY: 0.208 AC XY: 15491 AN XY: 74322

African (AFR) AF: 0.366 AC: 15161 AN: 41438

American (AMR) AF: 0.271 AC: 4139 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 516 AN: 3470

East Asian (EAS) AF: 0.373 AC: 1918 AN: 5140

South Asian (SAS) AF: 0.217 AC: 1044 AN: 4816

European-Finnish (FIN) AF: 0.111 AC: 1173 AN: 10604

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0996 AC: 6774 AN: 67982

Other (OTH) AF: 0.193 AC: 408 AN: 2110

Alfa AF: 0.124 Hom.: 2480

Bravo AF: 0.224

Asia WGS AF: 0.296 AC: 1030 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Glycogen storage disease, type V (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.044
DANN	Benign	0.59
PhyloP100		-3.8
PromoterAI		0.064	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs477549; hg19: chr11-64527080; COSMIC: COSV51218025; COSMIC: COSV51218025;