Genetic Variant NM_005609.4:c.1184C>A (chr11-64753934-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1PM2PP2BP4_Moderate

The NM_005609.4(PYGM):c.1184C>A(p.Thr395Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T395M) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PYGM
NM_005609.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.07

Publications

8 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_005609.4

PM2

Very rare variant in population databases, with high coverage;

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=0.16585779).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGM	NM_005609.4 link	c.1184C>A	p.Thr395Lys	missense_variant	Exon 10 of 20	ENST00000164139.4	NP_005600.1	P11217-1
PYGM	NM_001164716.1 link	c.920C>A	p.Thr307Lys	missense_variant	Exon 8 of 18		NP_001158188.1	P11217-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PYGM	ENST00000164139.4 link	c.1184C>A	p.Thr395Lys	missense_variant	Exon 10 of 20	1	NM_005609.4	ENSP00000164139.3	P11217-1
PYGM	ENST00000377432.7 link	c.920C>A	p.Thr307Lys	missense_variant	Exon 8 of 18	2		ENSP00000366650.3	P11217-2
PYGM	ENST00000460413.1 link	n.261C>A		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1446698

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718220

African (AFR)

AF:

0.00

AC:

AN:

33224

American (AMR)

AF:

0.00

AC:

AN:

42784

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25862

East Asian (EAS)

AF:

0.00

AC:

AN:

39102

South Asian (SAS)

AF:

0.00

AC:

AN:

83844

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51848

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104500

Other (OTH)

AF:

0.00

AC:

AN:

59794

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Uncertain

0.086

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.26

.;T

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.45

MutationAssessor

Benign

-1.9

.;N

PhyloP100

2.1

PrimateAI

Benign

0.48

PROVEAN

Benign

1.8

N;N

REVEL

Uncertain

0.46

Sift

Benign

0.83

T;T

Sift4G

Benign

0.73

T;T

Polyphen

0.0

.;B

Vest4

0.34

MutPred

0.43

.;Gain of methylation at T395 (P = 0.0211);

MVP

0.83

MPC

0.27

ClinPred

0.44

GERP RS

5.0

Varity_R

0.22

gMVP

0.58

Mutation Taster

=91/9

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over