Genetic Variant PYGM:p.Met1? (chr11-64759898-T-C) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PS1_ModeratePP5_Very_Strong

The NM_005609.4(PYGM):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000616 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PYGM
NM_005609.4 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 5.93

Publications

13 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: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

PYGM links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 47 pathogenic variants. Next in-frame start position is after 92 codons. Genomic position: 64758674. Lost 0.108 part of the original CDS.

PS1

Another start lost variant in NM_005609.4 (PYGM) was described as [Pathogenic] in ClinVar

PP5

Variant 11-64759898-T-C is Pathogenic according to our data. Variant chr11-64759898-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005609.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGM	NM_005609.4	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 20	NP_005600.1	P11217-1
	PYGM	NM_001164716.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 18	NP_001158188.1	P11217-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PYGM	ENST00000164139.4	TSL:1 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 20	ENSP00000164139.3	P11217-1
PYGM	ENST00000967737.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 21	ENSP00000637796.1
PYGM	ENST00000938870.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 20	ENSP00000608929.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

250944

AF XY:

0.0000295

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461654

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53242

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111970

Other (OTH)

AF:

0.0000662

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glycogen storage disease, type V (7)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.94

PhyloP100

5.9

PROVEAN

Benign

-1.9

REVEL

Pathogenic

0.77

Sift

Benign

0.22

Sift4G

Uncertain

0.039

Polyphen

1.0

Vest4

0.84

MutPred

1.0

Loss of MoRF binding (P = 0.1195)

MVP

0.94

ClinPred

0.95

GERP RS

5.4

PromoterAI

-0.19

Neutral

(source)

Varity_R

0.51

gMVP

0.67

Mutation Taster

=6/194

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over