rs114468011

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2BP4_ModerateBP6BS2_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). Synonymous variant affecting the same amino acid position (i.e. N283N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00081 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 6 hom. )

Consequence

PYGM
NM_005609.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:6

Conservation

PhyloP100: 8.02

Publications

6 publications found

Variant links:

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: STRONG, SUPPORTIVE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp

PYGM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 37 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 0.046884 (below the threshold of 3.09). Trascript score misZ: 1.6804 (below the threshold of 3.09). GenCC associations: The gene is linked to glycogen storage disease V.

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 VariationId is 167552.

BS2

High Homozygotes in GnomAdExome4 at 6 AR,AD 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 rank	MANE	Protein	UniProt
PYGM	NM_005609.4 link	c.848A>G	p.Asn283Ser	missense_variant	Exon 7 of 20	ENST00000164139.4	NP_005600.1	P11217-1
PYGM	NM_001164716.1 link	c.584A>G	p.Asn195Ser	missense_variant	Exon 5 of 18		NP_001158188.1	P11217-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYGM	ENST00000164139.4 link	c.848A>G	p.Asn283Ser	missense_variant	Exon 7 of 20	1	NM_005609.4	ENSP00000164139.3		P11217-1
PYGM	ENST00000377432.7 link	c.584A>G	p.Asn195Ser	missense_variant	Exon 5 of 18	2		ENSP00000366650.3		P11217-2

Frequencies

GnomAD3 genomes

AF:

0.000809

AC:

123

AN:

152122

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00133

AC:

334

AN:

251388

AF XY:

0.00142

show subpopulations

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 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.:

Cov.:

AF XY:

0.00125

AC XY:

910

AN XY:

727052

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33472

American (AMR)

AF:

0.000268

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00264

AC:

AN:

26136

East Asian (EAS)

AF:

0.000277

AC:

AN:

39700

South Asian (SAS)

AF:

0.00121

AC:

104

AN:

86244

European-Finnish (FIN)

AF:

0.000693

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00131

AC:

1455

AN:

1111664

Other (OTH)

AF:

0.00123

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

108

217

325

434

542

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

144

192

240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000808

AC:

123

AN:

152240

Hom.:

Cov.:

AF XY:

0.000833

AC XY:

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41556

American (AMR)

AF:

0.0000654

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

3468

East Asian (EAS)

AF:

0.000387

AC:

AN:

5172

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00123

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00113

Hom.:

Bravo

AF:

0.000684

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00170

AC:

206

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00125

EpiControl

AF:

0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glycogen storage disease, type V

Uncertain:2Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

May 18, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:2Benign:2

Jun 03, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 09, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PYGM: BS2 -

Dec 05, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS2 -

PYGM-related disorder

Benign:1

Jul 08, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

.;D

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.18

T;T

MetaSVM

Pathogenic

0.89

MutationAssessor

Uncertain

2.8

.;M

PhyloP100

8.0

PrimateAI

Uncertain

0.70

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

GERP RS

5.6

Varity_R

0.71

gMVP

0.67

Mutation Taster

=38/62

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over