chr11-64752071-C-T

Position:

• chr11-64752071-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005609.4(PYGM):​c.1621G>A​(p.Glu541Lys) variant causes a missense, 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PYGM NM_005609.4 missense, splice_region
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.87

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYGM	NM_005609.4	c.1621G>A	p.Glu541Lys	missense_variant, splice_region_variant	14/20	ENST00000164139.4	NP_005600.1
PYGM	NM_001164716.1	c.1357G>A	p.Glu453Lys	missense_variant, splice_region_variant	12/18		NP_001158188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYGM	ENST00000164139.4	c.1621G>A	p.Glu541Lys	missense_variant, splice_region_variant	14/20	1	NM_005609.4	ENSP00000164139.3
PYGM	ENST00000377432.7	c.1357G>A	p.Glu453Lys	missense_variant, splice_region_variant	12/18	2		ENSP00000366650.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	.;D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.9	.;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.61
Sift	Benign	0.084	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.28	.;B
Vest4		0.88
MutPred		0.47		.;Gain of MoRF binding (P = 0.0022);
MVP		0.95
MPC		0.27
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.71
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.010		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: rs119103257; hg19: chr11-64519543; COSMIC: COSV105034917; COSMIC: COSV105034917;