Genetic Variant PYGM:c.999+99T>C (chr11-64754594-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005609.4(PYGM):c.999+99T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.868 in 1,496,630 control chromosomes in the GnomAD database, including 573,404 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.77 ( 46837 hom., cov: 30)

Exomes 𝑓: 0.88 ( 526567 hom. )

Consequence

PYGM
NM_005609.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.462

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 11-64754594-A-G is Benign according to our data. Variant chr11-64754594-A-G is described in ClinVar as [Benign]. Clinvar id is 1177463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.902 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGM	NM_005609.4 link	c.999+99T>C		intron_variant	Intron 8 of 19	ENST00000164139.4	NP_005600.1	P11217-1
PYGM	NM_001164716.1 link	c.735+99T>C		intron_variant	Intron 6 of 17		NP_001158188.1	P11217-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PYGM	ENST00000164139.4 link	c.999+99T>C	intron_variant	Intron 8 of 19	1	NM_005609.4	ENSP00000164139.3	P11217-1
PYGM	ENST00000377432.7 link	c.735+99T>C	intron_variant	Intron 6 of 17	2		ENSP00000366650.3	P11217-2
PYGM	ENST00000460413.1 link	n.-173T>C	upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.766

AC:

116191

AN:

151704

Hom.:

46839

Cov.:

show subpopulations

Gnomad AFR

AF:

0.511

Gnomad AMI

AF:

0.974

Gnomad AMR

AF:

0.730

Gnomad ASJ

AF:

0.866

Gnomad EAS

AF:

0.621

Gnomad SAS

AF:

0.801

Gnomad FIN

AF:

0.890

Gnomad MID

AF:

0.915

Gnomad NFE

AF:

0.908

Gnomad OTH

AF:

0.800

GnomAD4 exome

AF:

0.880

AC:

1183566

AN:

1344808

Hom.:

526567

Cov.:

AF XY:

0.880

AC XY:

587768

AN XY:

668206

show subpopulations

Gnomad4 AFR exome

AF:

0.505

Gnomad4 AMR exome

AF:

0.691

Gnomad4 ASJ exome

AF:

0.872

Gnomad4 EAS exome

AF:

0.599

Gnomad4 SAS exome

AF:

0.811

Gnomad4 FIN exome

AF:

0.890

Gnomad4 NFE exome

AF:

0.914

Gnomad4 OTH exome

AF:

0.858

GnomAD4 genome

AF:

0.766

AC:

116235

AN:

151822

Hom.:

46837

Cov.:

AF XY:

0.763

AC XY:

56631

AN XY:

74196

show subpopulations

Gnomad4 AFR

AF:

0.510

Gnomad4 AMR

AF:

0.730

Gnomad4 ASJ

AF:

0.866

Gnomad4 EAS

AF:

0.620

Gnomad4 SAS

AF:

0.800

Gnomad4 FIN

AF:

0.890

Gnomad4 NFE

AF:

0.908

Gnomad4 OTH

AF:

0.797

Alfa

AF:

0.789

Hom.:

3860

Bravo

AF:

0.741

Asia WGS

AF:

0.699

AC:

2428

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Glycogen storage disease, type V

Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

2.0

DANN

Benign

0.60

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

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