11-64746663-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005609.4(PYGM):c.2525T>A(p.Ile842Asn) variant causes a missense 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PYGM NM_005609.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.36

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20173535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGM	NM_005609.4	c.2525T>A	p.Ile842Asn	missense_variant	20/20	ENST00000164139.4
PYGM	NM_001164716.1	c.2261T>A	p.Ile754Asn	missense_variant	18/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGM	ENST00000164139.4	c.2525T>A	p.Ile842Asn	missense_variant	20/20	1	NM_005609.4	P1
PYGM	ENST00000377432.7	c.2261T>A	p.Ile754Asn	missense_variant	18/18	2
PYGM	ENST00000483742.1	n.1878T>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glycogen storage disease, type V Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 18, 2022

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 842 of the PYGM protein (p.Ile842Asn). This variant has not been reported in the literature in individuals affected with PYGM-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
Cadd	Benign	22
Dann	Benign	0.96
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.69	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.33	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.82	N;N
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.81	.;P
Vest4		0.42
MutPred		0.24		.;Loss of stability (P = 0.0148);
MVP		0.63
MPC		0.40
ClinPred		0.32	T
GERP RS		3.2
Varity_R		0.26
gMVP		0.54

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-64514135;