rs71581787

Variant names:

• chr11-64753934-G-A
• rs71581787
• NM_005609.4:c.1184C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-64753934-G-A
• chr11-64753934-G-C
• chr11-64753934-G-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_005609.4(PYGM):​c.1184C>T​(p.Thr395Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,598,754 control chromosomes in the GnomAD database, including 144 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T395T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (71 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (73 hom.)
• Consequence: PYGM NM_005609.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.07
• 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 -17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_005609.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 37 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 0.046884 (below the threshold of 3.09). Trascript score misZ: 1.6804 (below the threshold of 3.09). GenCC associations: The gene is linked to glycogen storage disease V.
• BP4: Computational evidence support a benign effect (MetaRNN=0.006409377).
• BP6: Variant 11-64753934-G-A is Benign according to our data. Variant chr11-64753934-G-A is described in ClinVar as Benign. ClinVar VariationId is 193682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0564 is higher than 0.05.

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.1184C>T	p.Thr395Met	missense	Exon 10 of 20	NP_005600.1
	PYGM	NM_001164716.1		c.920C>T	p.Thr307Met	missense	Exon 8 of 18	NP_001158188.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGM	ENST00000164139.4	TSL:1 MANE Select	c.1184C>T	p.Thr395Met	missense	Exon 10 of 20	ENSP00000164139.3
	PYGM	ENST00000967737.1		c.1283C>T	p.Thr428Met	missense	Exon 11 of 21	ENSP00000637796.1
	PYGM	ENST00000938870.1		c.1100C>T	p.Thr367Met	missense	Exon 10 of 20	ENSP00000608929.1

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2697 AN: 151942 Hom.: 70 Cov.: 31

Gnomad AFR AF: 0.0583

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00497 AC: 1112 AN: 223762 AF XY: 0.00372

Gnomad AFR exome AF: 0.0594

Gnomad AMR exome AF: 0.00489

Gnomad ASJ exome AF: 0.00105

Gnomad EAS exome AF: 0.000118

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.00501

GnomAD4 exome AF: 0.00242 AC: 3507 AN: 1446694 Hom.: 73 Cov.: 37 AF XY: 0.00217 AC XY: 1556 AN XY: 718220

African (AFR) AF: 0.0622 AC: 2065 AN: 33222

American (AMR) AF: 0.00559 AC: 239 AN: 42780

Ashkenazi Jewish (ASJ) AF: 0.00159 AC: 41 AN: 25862

East Asian (EAS) AF: 0.0000511 AC: 2 AN: 39102

South Asian (SAS) AF: 0.000227 AC: 19 AN: 83844

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51848

Middle Eastern (MID) AF: 0.00801 AC: 46 AN: 5740

European-Non Finnish (NFE) AF: 0.000691 AC: 763 AN: 1104502

Other (OTH) AF: 0.00555 AC: 332 AN: 59794

GnomAD4 genome AF: 0.0178 AC: 2705 AN: 152060 Hom.: 71 Cov.: 31 AF XY: 0.0171 AC XY: 1274 AN XY: 74300

African (AFR) AF: 0.0583 AC: 2422 AN: 41512

American (AMR) AF: 0.0115 AC: 176 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00103 AC: 70 AN: 67848

Other (OTH) AF: 0.0118 AC: 25 AN: 2110

Alfa AF: 0.00765 Hom.: 46

Bravo AF: 0.0205

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0523 AC: 230

ESP6500EA AF: 0.000699 AC: 6

ExAC AF: 0.00558 AC: 675

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Glycogen storage disease, type V (4)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.019
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.1
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.76	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.036	B
Vest4		0.38
MVP		0.94
MPC		0.49
ClinPred		0.017	T
GERP RS		5.0
Varity_R		0.10
gMVP		0.47
Mutation Taster		=98/2	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: rs71581787; hg19: chr11-64521406;