rs114468011

Positions:

• chr11-64755280-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BS2_Supporting

The NM_005609.4(PYGM):​c.848A>G​(p.Asn283Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,613,688 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (6 hom.)
• Consequence: PYGM NM_005609.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6
• Conservation: PhyloP100: 8.02

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1810683).
• BP6: Variant 11-64755280-T-C is Benign according to our data. Variant chr11-64755280-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167552.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=4}.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYGM	NM_005609.4	c.848A>G	p.Asn283Ser	missense_variant	7/20	ENST00000164139.4	NP_005600.1
PYGM	NM_001164716.1	c.584A>G	p.Asn195Ser	missense_variant	5/18		NP_001158188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYGM	ENST00000164139.4	c.848A>G	p.Asn283Ser	missense_variant	7/20	1	NM_005609.4	ENSP00000164139.3
PYGM	ENST00000377432.7	c.584A>G	p.Asn195Ser	missense_variant	5/18	2		ENSP00000366650.3

Frequencies

GnomAD3 genomes AF: 0.000809 AC: 123 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00133 AC: 334 AN: 251388 Hom.: 4 AF XY: 0.00142 AC XY: 193 AN XY: 135888

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.000652

Gnomad SAS exome AF: 0.00163

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00190

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00121 AC: 1769 AN: 1461448 Hom.: 6 Cov.: 32 AF XY: 0.00125 AC XY: 910 AN XY: 727052

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00264

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.00121

Gnomad4 FIN exome AF: 0.000693

Gnomad4 NFE exome AF: 0.00131

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.000808 AC: 123 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000833 AC XY: 62 AN XY: 74420

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00123

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00128 Hom.: 0

Bravo AF: 0.000684

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00170 AC: 206

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glycogen storage disease, type V Uncertain:2 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	PYGM: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 05, 2022	BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 09, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2019	- -

PYGM-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	.;D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.8	.;M
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Pathogenic	0.74
Sift	Benign	0.042	D;T
Sift4G	Uncertain	0.039	D;D
Polyphen		0.96	.;D
Vest4		0.82
MVP		0.97
MPC		0.33
ClinPred		0.054	T
GERP RS		5.6
Varity_R		0.71
gMVP		0.67

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

LitVar

Other links and lift over

dbSNP: rs114468011; hg19: chr11-64522752;