rs11231866

chr11-64753682-G-Achr11-64753682-G-C

Variant summary

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

The NM_005609.4(PYGM):c.1240C>T(p.Arg414Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,605,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R414G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: PYGM NM_005609.4 missense, splice_region
• Scores: Splicing: ADA: 0.003679
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0260

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, 0.768

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGM	NM_005609.4	c.1240C>T	p.Arg414Trp	missense_variant, splice_region_variant	11/20	ENST00000164139.4
PYGM	NM_001164716.1	c.976C>T	p.Arg326Trp	missense_variant, splice_region_variant	9/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGM	ENST00000164139.4	c.1240C>T	p.Arg414Trp	missense_variant, splice_region_variant	11/20	1	NM_005609.4	P1
PYGM	ENST00000377432.7	c.976C>T	p.Arg326Trp	missense_variant, splice_region_variant	9/18	2
PYGM	ENST00000460413.1	n.317C>T		splice_region_variant, non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152070 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000868 AC: 2 AN: 230338 Hom.: 0 AF XY: 0.00000790 AC XY: 1 AN XY: 126638

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: 0.0000341

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000980

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000895 AC: 13 AN: 1453150 Hom.: 0 Cov.: 45 AF XY: 0.00000415 AC XY: 3 AN XY: 722598

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: 0.0000117

Gnomad4 FIN exome AF: 0.0000202

Gnomad4 NFE exome AF: 0.00000811

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74402

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000448 Hom.: 7

Bravo AF: 0.0000264

ExAC AF: 0.00000830 AC: 1

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

Jun 17, 2022

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 414 of the PYGM protein (p.Arg414Trp). This variant is present in population databases (rs11231866, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with PYGM-related conditions. 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: "Possibly Damaging"; Align-GVGD: "Not Available"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Uncertain	0.090
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.57	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	0.42	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		0.90	.;P
Vest4		0.69
MutPred		0.48		.;Gain of catalytic residue at L412 (P = 0.0634);
MVP		0.95
MPC		0.65
ClinPred		0.92	D
GERP RS		1.8
Varity_R		0.60
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0037
dbscSNV1_RF	Benign	0.20
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: rs11231866; hg19: chr11-64521154;