11-64758514-A-G

Position:

chr11-64758514-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_005609.4(PYGM):c.347T>C(p.Leu116Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,938 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 predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L116V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

PYGM
NM_005609.4 missense, splice_region

Scores

Splicing: ADA: 0.2407

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 7.51

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 Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

PP5

Variant 11-64758514-A-G is Pathogenic according to our data. Variant chr11-64758514-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 551567.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=3}. Variant chr11-64758514-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGM	NM_005609.4 linkuse as main transcript	c.347T>C	p.Leu116Pro	missense_variant, splice_region_variant	3/20	ENST00000164139.4
PYGM	NM_001164716.1 linkuse as main transcript	c.244-248T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGM	ENST00000164139.4 linkuse as main transcript	c.347T>C	p.Leu116Pro	missense_variant, splice_region_variant	3/20	1	NM_005609.4	P1	P11217-1
PYGM	ENST00000377432.7 linkuse as main transcript	c.244-248T>C		intron_variant		2			P11217-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

251268

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461832

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000803

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000993

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glycogen storage disease, type V

Pathogenic:2Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 16, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 12, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 116 of the PYGM protein (p.Leu116Pro). This variant is present in population databases (rs776680924, gnomAD 0.1%). This missense change has been observed in individual(s) with glycogen storage disease and/or McArdle disease (PMID: 10417800, 29143597, 30011114, 34215481; Invitae). This variant is also known as L115P. ClinVar contains an entry for this variant (Variation ID: 551567). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 07, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-5.4

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.99

MutPred

0.90

Loss of stability (P = 0.0086);

MVP

0.99

MPC

1.1

ClinPred

0.90

GERP RS

5.1

Varity_R

0.97

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.24

dbscSNV1_RF

Benign

0.40

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

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