rs752851284

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000164139.4(PYGM):​c.425-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,502 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 predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PYGM
ENST00000164139.4 splice_acceptor

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 8.02
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 Pathogenic. Variant got 18 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.8, offset of -22, new splice context is: ccttgctgggtccctgacAGcca. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-64758351-T-C is Pathogenic according to our data. Variant chr11-64758351-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PYGMNM_005609.4 linkuse as main transcriptc.425-2A>G splice_acceptor_variant ENST00000164139.4 NP_005600.1
PYGMNM_001164716.1 linkuse as main transcriptc.244-85A>G intron_variant NP_001158188.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PYGMENST00000164139.4 linkuse as main transcriptc.425-2A>G splice_acceptor_variant 1 NM_005609.4 ENSP00000164139 P1P11217-1
PYGMENST00000377432.7 linkuse as main transcriptc.244-85A>G intron_variant 2 ENSP00000366650 P11217-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251086
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135744
show subpopulations
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1461502
Hom.:
0
Cov.:
34
AF XY:
0.00000550
AC XY:
4
AN XY:
727064
show subpopulations
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Glycogen storage disease, type V Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJan 23, 2024- -
Likely pathogenic, no assertion criteria providedclinical testingNatera, Inc.Oct 19, 2021- -
Likely pathogenic, criteria provided, single submitterclinical testingCounsylFeb 16, 2016- -
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 05, 2021In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PYGM are known to be pathogenic (PMID: 8316268, 16786513). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with PYGM-related disease. ClinVar contains an entry for this variant (Variation ID: 370481). This variant is present in population databases (rs752851284, ExAC 0.002%). This sequence change affects an acceptor splice site in intron 3 of the PYGM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.30
CADD
Pathogenic
32
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Pathogenic
0.99
D
MutationTaster
Benign
1.0
D;D
GERP RS
5.4

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.91
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.99
Position offset: -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: rs752851284; hg19: chr11-64525823; API