rs589691

Variant names:

Variant summary

Our verdict is The variant received -16 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_Strong

The NM_005609.4(PYGM):c.660+35G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.849 (AC=1,369,127) in the gnomAD database across 1,613,552 control chromosomes, including 597,641 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.904. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 42040 hom., cov: 32)

Exomes 𝑓: 0.86 ( 555601 hom. )

Consequence

PYGM
NM_005609.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.270

Publications

28 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, Orphanet, Natera, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
disorder of glycogen metabolism
Inheritance: AD Classification: MODERATE Submitted by: PanelApp Australia

PYGM links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_005609.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -16 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.9035 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGM	NM_005609.4	MANE Select	c.660+35G>A		intron	N/A	NP_005600.1	P11217-1
	PYGM	NM_001164716.1		c.396+35G>A		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.660+35G>A	intron	N/A	ENSP00000164139.3	P11217-1
PYGM	ENST00000967737.1		c.660+35G>A	intron	N/A	ENSP00000637796.1
PYGM	ENST00000938870.1		c.660+35G>A	intron	N/A	ENSP00000608929.1

Frequencies

GnomAD3 genomes

AF:

0.697

AC:

106032

AN:

152028

Hom.:

42049

Cov.:

show subpopulations

Gnomad AFR

AF:

0.302

Gnomad AMI

AF:

0.967

Gnomad AMR

AF:

0.683

Gnomad ASJ

AF:

0.846

Gnomad EAS

AF:

0.618

Gnomad SAS

AF:

0.792

Gnomad FIN

AF:

0.889

Gnomad MID

AF:

0.839

Gnomad NFE

AF:

0.898

Gnomad OTH

AF:

0.730

GnomAD2 exomes

AF:

0.793

AC:

198705

AN:

250478

AF XY:

0.810

show subpopulations

Gnomad AFR exome

AF:

0.295

Gnomad AMR exome

AF:

0.667

Gnomad ASJ exome

AF:

0.851

Gnomad EAS exome

AF:

0.616

Gnomad FIN exome

AF:

0.885

Gnomad NFE exome

AF:

0.902

Gnomad OTH exome

AF:

0.840

GnomAD4 exome

AF:

0.864

AC:

1263079

AN:

1461406

Hom.:

555601

Cov.:

AF XY:

0.865

AC XY:

628821

AN XY:

726994

show subpopulations

African (AFR)

AF:

0.288

AC:

9631

AN:

33468

American (AMR)

AF:

0.664

AC:

29654

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.848

AC:

22167

AN:

26130

East Asian (EAS)

AF:

0.597

AC:

23703

AN:

39686

South Asian (SAS)

AF:

0.804

AC:

69324

AN:

86244

European-Finnish (FIN)

AF:

0.888

AC:

47317

AN:

53290

Middle Eastern (MID)

AF:

0.854

AC:

4921

AN:

5762

European-Non Finnish (NFE)

AF:

0.905

AC:

1006163

AN:

1111764

Other (OTH)

AF:

0.831

AC:

50199

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

8758

17515

26273

35030

43788

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21244

42488

63732

84976

106220

<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

AF:

0.697

AC:

106048

AN:

152146

Hom.:

42040

Cov.:

AF XY:

0.697

AC XY:

51815

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.302

AC:

12526

AN:

41480

American (AMR)

AF:

0.683

AC:

10444

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.846

AC:

2939

AN:

3472

East Asian (EAS)

AF:

0.617

AC:

3178

AN:

5148

South Asian (SAS)

AF:

0.792

AC:

3829

AN:

4834

European-Finnish (FIN)

AF:

0.889

AC:

9430

AN:

10608

Middle Eastern (MID)

AF:

0.837

AC:

246

AN:

294

European-Non Finnish (NFE)

AF:

0.898

AC:

61040

AN:

68004

Other (OTH)

AF:

0.728

AC:

1534

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1156

2312

3467

4623

5779

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

790

1580

2370

3160

3950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.834

Hom.:

162259

Bravo

AF:

0.665

Asia WGS

AF:

0.680

AC:

2365

AN:

3478

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.578

AC:

70829

AN:

122576

Turkish Variome

AF:

0.852

AC:

5690

AN:

6680

Hom.:

2429

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.597

AC:

5350

AN:

8960

Hom.:

1622

ABraOM SABE-WGS-1171

AF:

0.725

AC:

1698

AN:

2342

Hom.:

644

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Glycogen storage disease, type V (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.0

(source)

DANN

Benign

0.30

PhyloP100

-0.27

Mutation Taster

=100/0

polymorphism (auto)

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over