11-64754594-A-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005609.4(PYGM):​c.999+99T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PYGM NM_005609.4 intron
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGM	NM_005609.4	c.999+99T>A		intron_variant	Intron 8 of 19	ENST00000164139.4	NP_005600.1
PYGM	NM_001164716.1	c.735+99T>A		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>A		intron_variant	Intron 8 of 19	1	NM_005609.4	ENSP00000164139.3
PYGM	ENST00000377432.7	c.735+99T>A		intron_variant	Intron 6 of 17	2		ENSP00000366650.3
PYGM	ENST00000460413.1	n.-173T>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000149 AC: 2 AN: 1345270 Hom.: 0 Cov.: 24 AF XY: 0.00000150 AC XY: 1 AN XY: 668412

African (AFR) AF: 0.00 AC: 0 AN: 30844

American (AMR) AF: 0.00 AC: 0 AN: 37120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24848

East Asian (EAS) AF: 0.00 AC: 0 AN: 36680

South Asian (SAS) AF: 0.00 AC: 0 AN: 79118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4056

European-Non Finnish (NFE) AF: 0.00000194 AC: 2 AN: 1031754

Other (OTH) AF: 0.00 AC: 0 AN: 56424

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 3953

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.66
PhyloP100		0.46

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;