NM_005609.4:c.2527T>A

Variant names:

• chr11-64746661-A-T
• rs1400353740
• NM_005609.4:c.2527T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_005609.4(PYGM):​c.2527T>A​(p.Ter843Argext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PYGM NM_005609.4 stop_lost
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.38
• Publications: 2 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_005609.4 Downstream stopcodon found after 51 codons.

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.2527T>A	p.Ter843Argext*?	stop_lost	Exon 20 of 20	NP_005600.1	P11217-1
	PYGM	NM_001164716.1		c.2263T>A	p.Ter755Argext*?	stop_lost	Exon 18 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.2527T>A	p.Ter843Argext*?	stop_lost	Exon 20 of 20	ENSP00000164139.3	P11217-1
	PYGM	ENST00000967737.1		c.2626T>A	p.Ter876Argext*?	stop_lost	Exon 21 of 21	ENSP00000637796.1
	PYGM	ENST00000938870.1		c.2443T>A	p.Ter815Argext*?	stop_lost	Exon 20 of 20	ENSP00000608929.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	Benign	-0.0095	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Benign	0.89
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.095
FATHMM_MKL	Benign	0.18	N
PhyloP100		2.4
Vest4		0.12
GERP RS		3.3
Mutation Taster		=11/189	disease causing

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: rs1400353740; hg19: chr11-64514133;