chr11-64752486-T-G

Position:

• chr11-64752486-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_005609.4(PYGM):​c.1537A>C​(p.Ile513Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I513V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PYGM NM_005609.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.72

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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-64752486-T-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.273337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGM	NM_005609.4	c.1537A>C	p.Ile513Leu	missense_variant	13/20	ENST00000164139.4
PYGM	NM_001164716.1	c.1273A>C	p.Ile425Leu	missense_variant	11/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGM	ENST00000164139.4	c.1537A>C	p.Ile513Leu	missense_variant	13/20	1	NM_005609.4	P1
PYGM	ENST00000377432.7	c.1273A>C	p.Ile425Leu	missense_variant	11/18	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251172 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135816

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461800 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.31	.;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.013
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	0.21	.;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.91	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.40	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.0	.;B
Vest4		0.44
MutPred		0.48		.;Gain of phosphorylation at S514 (P = 0.2024);
MVP		0.85
MPC		0.39
ClinPred		0.36	T
GERP RS		5.8
Varity_R		0.56
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs139570786; hg19: chr11-64519958;