11-64754594-A-G

Variant names:

• chr11-64754594-A-G
• rs625172
• NM_005609.4:c.999+99T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.462
• Publications: 8 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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	c.999+99T>C		intron_variant	Intron 8 of 19	ENST00000164139.4	NP_005600.1
PYGM	NM_001164716.1	c.735+99T>C		intron_variant	Intron 6 of 17		NP_001158188.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.766 AC: 116191 AN: 151704 Hom.: 46839 Cov.: 30

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.: 24 AF XY: 0.880 AC XY: 587768 AN XY: 668206

African (AFR) AF: 0.505 AC: 15569 AN: 30816

American (AMR) AF: 0.691 AC: 25644 AN: 37114

Ashkenazi Jewish (ASJ) AF: 0.872 AC: 21662 AN: 24840

East Asian (EAS) AF: 0.599 AC: 21945 AN: 36662

South Asian (SAS) AF: 0.811 AC: 64135 AN: 79096

European-Finnish (FIN) AF: 0.890 AC: 39522 AN: 44402

Middle Eastern (MID) AF: 0.905 AC: 3667 AN: 4054

European-Non Finnish (NFE) AF: 0.914 AC: 942998 AN: 1031412

Other (OTH) AF: 0.858 AC: 48424 AN: 56412

GnomAD4 genome AF: 0.766 AC: 116235 AN: 151822 Hom.: 46837 Cov.: 30 AF XY: 0.763 AC XY: 56631 AN XY: 74196

African (AFR) AF: 0.510 AC: 21080 AN: 41294

American (AMR) AF: 0.730 AC: 11154 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.866 AC: 3007 AN: 3472

East Asian (EAS) AF: 0.620 AC: 3176 AN: 5120

South Asian (SAS) AF: 0.800 AC: 3852 AN: 4812

European-Finnish (FIN) AF: 0.890 AC: 9421 AN: 10584

Middle Eastern (MID) AF: 0.918 AC: 270 AN: 294

European-Non Finnish (NFE) AF: 0.908 AC: 61706 AN: 67950

Other (OTH) AF: 0.797 AC: 1681 AN: 2108

Alfa AF: 0.770 Hom.: 3953

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

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
PhyloP100		0.46
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs625172; hg19: chr11-64522066; COSMIC: COSV51222856; COSMIC: COSV51222856;