chr11-64758371-G-A

Variant names:

• chr11-64758371-G-A
• rs61884454
• NM_005609.4:c.425-22C>T

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.425-22C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0306 in 1,612,576 control chromosomes in the GnomAD database, including 1,164 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (75 hom., cov: 32)
  • Exomes 𝑓: 0.031 (1089 hom.)
• Consequence: PYGM NM_005609.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.00500
• Publications: 3 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=-0.8).
• BP6: Variant 11-64758371-G-A is Benign according to our data. Variant chr11-64758371-G-A is described in ClinVar as Benign. ClinVar VariationId is 259836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGM	NM_005609.4	c.425-22C>T		intron_variant	Intron 3 of 19	ENST00000164139.4	NP_005600.1
PYGM	NM_001164716.1	c.244-105C>T		intron_variant	Intron 1 of 17		NP_001158188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYGM	ENST00000164139.4	c.425-22C>T		intron_variant	Intron 3 of 19	1	NM_005609.4	ENSP00000164139.3
PYGM	ENST00000377432.7	c.244-105C>T		intron_variant	Intron 1 of 17	2		ENSP00000366650.3

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 3793 AN: 152064 Hom.: 73 Cov.: 32

Gnomad AFR AF: 0.00814

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0676

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.0166

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0302

Gnomad OTH AF: 0.0230

GnomAD2 exomes AF: 0.0370 AC: 9269 AN: 250742 AF XY: 0.0330

Gnomad AFR exome AF: 0.00764

Gnomad AMR exome AF: 0.134

Gnomad ASJ exome AF: 0.00526

Gnomad EAS exome AF: 0.000490

Gnomad FIN exome AF: 0.0193

Gnomad NFE exome AF: 0.0299

Gnomad OTH exome AF: 0.0339

GnomAD4 exome AF: 0.0312 AC: 45513 AN: 1460394 Hom.: 1089 Cov.: 34 AF XY: 0.0304 AC XY: 22073 AN XY: 726598

African (AFR) AF: 0.00511 AC: 171 AN: 33464

American (AMR) AF: 0.124 AC: 5551 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 173 AN: 26134

East Asian (EAS) AF: 0.00139 AC: 55 AN: 39696

South Asian (SAS) AF: 0.0146 AC: 1256 AN: 86232

European-Finnish (FIN) AF: 0.0187 AC: 989 AN: 52784

Middle Eastern (MID) AF: 0.0104 AC: 60 AN: 5768

European-Non Finnish (NFE) AF: 0.0320 AC: 35585 AN: 1111224

Other (OTH) AF: 0.0277 AC: 1673 AN: 60370

GnomAD4 genome AF: 0.0250 AC: 3803 AN: 152182 Hom.: 75 Cov.: 32 AF XY: 0.0247 AC XY: 1835 AN XY: 74406

African (AFR) AF: 0.00811 AC: 337 AN: 41530

American (AMR) AF: 0.0682 AC: 1042 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5172

South Asian (SAS) AF: 0.0176 AC: 85 AN: 4828

European-Finnish (FIN) AF: 0.0166 AC: 176 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0302 AC: 2052 AN: 67974

Other (OTH) AF: 0.0223 AC: 47 AN: 2108

Alfa AF: 0.0191 Hom.: 24

Bravo AF: 0.0296

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jan 29, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Dec 16, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	13
DANN	Benign	0.70
PhyloP100		-0.0050
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61884454; hg19: chr11-64525843;