11-64753633-G-T

Variant names:

• chr11-64753633-G-T
• rs1212604
• NM_005609.4:c.1289C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_005609.4(PYGM):​c.1289C>A​(p.Ser430*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S430S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PYGM NM_005609.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.97
• Publications: 0 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: Pathogenic. The variant received 10 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

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.1289C>A	p.Ser430*	stop_gained	Exon 11 of 20	NP_005600.1	P11217-1
	PYGM	NM_001164716.1		c.1025C>A	p.Ser342*	stop_gained	Exon 9 of 18	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.1289C>A	p.Ser430*	stop_gained	Exon 11 of 20	ENSP00000164139.3	P11217-1
	PYGM	ENST00000967737.1		c.1388C>A	p.Ser463*	stop_gained	Exon 12 of 21	ENSP00000637796.1
	PYGM	ENST00000938870.1		c.1205C>A	p.Ser402*	stop_gained	Exon 11 of 20	ENSP00000608929.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456572 Hom.: 0 Cov.: 45 AF XY: 0.00 AC XY: 0 AN XY: 724558

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 85842

European-Finnish (FIN) AF: 0.0000201 AC: 1 AN: 49750

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111400

Other (OTH) AF: 0.00 AC: 0 AN: 60198

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	48
DANN	Uncertain	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		10
Vest4		0.90
GERP RS		4.9
Mutation Taster		=1/199	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.45		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1212604; hg19: chr11-64521105;