rs119103257

Variant names:

• chr11-64752071-C-A
• rs119103257
• NM_005609.4:c.1621G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-64752071-C-A
• chr11-64752071-C-T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PM2 PP3_Moderate PP5

The NM_005609.4(PYGM):​c.1621G>T​(p.Glu541*) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. E541E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PYGM NM_005609.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.87
• Publications: 1 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: Pathogenic. The variant received 13 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 11-64752071-C-A is Pathogenic according to our data. Variant chr11-64752071-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2310.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGM	NM_005609.4	MANE Select	c.1621G>T	p.Glu541*	stop_gained splice_region	Exon 14 of 20	NP_005600.1
	PYGM	NM_001164716.1		c.1357G>T	p.Glu453*	stop_gained splice_region	Exon 12 of 18	NP_001158188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGM	ENST00000164139.4	TSL:1 MANE Select	c.1621G>T	p.Glu541*	stop_gained splice_region	Exon 14 of 20	ENSP00000164139.3
	PYGM	ENST00000377432.7	TSL:2	c.1357G>T	p.Glu453*	stop_gained splice_region	Exon 12 of 18	ENSP00000366650.3
	PYGM	ENST00000462303.1	TSL:2	n.-56G>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Glycogen storage disease, type V (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.9
Vest4		0.95
GERP RS		5.9
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
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: rs119103257; hg19: chr11-64519543;