rs113806080

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM1PP3BP4_StrongBP6_Very_StrongBS2

The NM_005609.4(PYGM):c.2009C>T(p.Ala670Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00419 in 1,614,162 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A670A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0043 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 22 hom. )

Consequence

PYGM
NM_005609.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 9.96

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_005609.4

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PrimateAI, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.020154238).

BP6

Variant 11-64750544-G-A is Benign according to our data. Variant chr11-64750544-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 194748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64750544-G-A is described in Lovd as [Likely_pathogenic]. Variant chr11-64750544-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGM	NM_005609.4 linkuse as main transcript	c.2009C>T	p.Ala670Val	missense_variant	17/20	ENST00000164139.4
PYGM	NM_001164716.1 linkuse as main transcript	c.1745C>T	p.Ala582Val	missense_variant	15/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGM	ENST00000164139.4 linkuse as main transcript	c.2009C>T	p.Ala670Val	missense_variant	17/20	1	NM_005609.4	P1	P11217-1
PYGM	ENST00000377432.7 linkuse as main transcript	c.1745C>T	p.Ala582Val	missense_variant	15/18	2			P11217-2

Frequencies

GnomAD3 genomes

AF:

0.00427

AC:

650

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0229

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00459

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00490

AC:

1231

AN:

251412

Hom.:

AF XY:

0.00481

AC XY:

654

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00332

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.0210

Gnomad NFE exome

AF:

0.00516

Gnomad OTH exome

AF:

0.00456

GnomAD4 exome

AF:

0.00419

AC:

6119

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00413

AC XY:

3003

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.00302

Gnomad4 ASJ exome

AF:

0.00191

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000603

Gnomad4 FIN exome

AF:

0.0194

Gnomad4 NFE exome

AF:

0.00416

Gnomad4 OTH exome

AF:

0.00313

GnomAD4 genome

AF:

0.00427

AC:

650

AN:

152306

Hom.:

Cov.:

AF XY:

0.00536

AC XY:

399

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000914

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.0229

Gnomad4 NFE

AF:

0.00459

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00405

Hom.:

Bravo

AF:

0.00263

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.00508

AC:

617

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00442

EpiControl

AF:

0.00332

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease, type V

Benign:6

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 14, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 14, 2021	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 11, 2014	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PYGM: PP3, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2019	This variant is associated with the following publications: (PMID: 24503134, 20108426, 33111339) -

PYGM-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2019

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

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

.;D

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D

MetaRNN

Benign

0.020

T;T

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

4.1

.;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.7

D;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.025

D;D

Sift4G

Uncertain

0.019

D;D

Polyphen

1.0

.;D

Vest4

0.86

MVP

0.96

MPC

0.84

ClinPred

0.065

GERP RS

4.9

Varity_R

0.72

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over