rs113806080

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

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 (★★).

Frequency

Genomes: 𝑓 0.0043 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0042 ( 22 hom. )

Consequence

PYGM
NM_005609.4 missense

Scores

11
5
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

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].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00427 (650/152306) while in subpopulation NFE AF= 0.00459 (312/68026). AF 95% confidence interval is 0.00417. There are 3 homozygotes in gnomad4. There are 399 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PYGMNM_005609.4 linkc.2009C>T p.Ala670Val missense_variant Exon 17 of 20 ENST00000164139.4 NP_005600.1 P11217-1
PYGMNM_001164716.1 linkc.1745C>T p.Ala582Val missense_variant Exon 15 of 18 NP_001158188.1 P11217-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PYGMENST00000164139.4 linkc.2009C>T p.Ala670Val missense_variant Exon 17 of 20 1 NM_005609.4 ENSP00000164139.3 P11217-1
PYGMENST00000377432.7 linkc.1745C>T p.Ala582Val missense_variant Exon 15 of 18 2 ENSP00000366650.3 P11217-2

Frequencies

GnomAD3 genomes
AF:
0.00427
AC:
650
AN:
152188
Hom.:
3
Cov.:
32
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.:
9
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.:
22
Cov.:
32
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.:
3
Cov.:
32
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.:
5
Bravo
AF:
0.00263
TwinsUK
AF:
0.00351
AC:
13
ALSPAC
AF:
0.00519
AC:
20
ESP6500AA
AF:
0.00136
AC:
6
ESP6500EA
AF:
0.00407
AC:
35
ExAC
AF:
0.00508
AC:
617
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00442
EpiControl
AF:
0.00332

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Glycogen storage disease, type V Benign:6
Dec 14, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 14, 2020
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

May 28, 2019
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 24, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 12, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:3
Dec 04, 2019
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24503134, 20108426, 33111339) -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PYGM: PP3, BS2 -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

not specified Benign:2
Dec 11, 2014
Eurofins Ntd Llc (ga)
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 15, 2019
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

PYGM-related disorder Benign:1
Nov 22, 2019
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
Pathogenic
0.80
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.78
.;D
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
D;D
MetaRNN
Benign
0.020
T;T
MetaSVM
Pathogenic
0.92
D
MutationAssessor
Pathogenic
4.1
.;H
PrimateAI
Pathogenic
0.81
D
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
T
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.

Other links and lift over

dbSNP: rs113806080; hg19: chr11-64518016; COSMIC: COSV99031554; COSMIC: COSV99031554; API