11-64753878-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong

The NM_005609.4(PYGM):c.1239+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000127 in 1,419,690 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: 31)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

PYGM
NM_005609.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

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

Conservation

PhyloP100: 7.28

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.05812574 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.5, offset of 32, new splice context is: gggGTgagg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PP5

Variant 11-64753878-C-T is Pathogenic according to our data. Variant chr11-64753878-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 569514.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.1239+1G>A		splice_donor intron	N/A	NP_005600.1	P11217-1
	PYGM	NM_001164716.1		c.975+1G>A		splice_donor intron	N/A	NP_001158188.1	P11217-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PYGM	ENST00000164139.4	TSL:1 MANE Select	c.1239+1G>A	splice_donor intron	N/A	ENSP00000164139.3	P11217-1
PYGM	ENST00000967737.1		c.1338+1G>A	splice_donor intron	N/A	ENSP00000637796.1
PYGM	ENST00000938870.1		c.1155+1G>A	splice_donor intron	N/A	ENSP00000608929.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000538

AC:

AN:

186020

AF XY:

0.0000100

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:

0.0000129

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000127

AC:

AN:

1419690

Hom.:

Cov.:

AF XY:

0.0000114

AC XY:

AN XY:

702390

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32544

American (AMR)

AF:

0.00

AC:

AN:

38784

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25414

East Asian (EAS)

AF:

0.00

AC:

AN:

37514

South Asian (SAS)

AF:

0.00

AC:

AN:

80962

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50016

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5472

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

1090240

Other (OTH)

AF:

0.0000340

AC:

AN:

58744

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

0.0000409

Hom.:

ExAC

AF:

0.00000834

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glycogen storage disease, type V (4)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

PhyloP100

7.3

GERP RS

5.0

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.54

Position offset: -3

DS_DL_spliceai

0.98

Position offset: 1

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