rs143759519

Variant names:

• chr14-50915919-G-A
• rs143759519
• NM_002863.5:c.1145C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 1P and 11B. PP3 BP4_Moderate BP6 BS1 BS2

The NM_002863.5(PYGL):​c.1145C>T​(p.Pro382Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00547 in 1,614,214 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0043 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (31 hom.)
• Consequence: PYGL NM_002863.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:6
• Conservation: PhyloP100: 9.97
• Publications: 17 publications found

Genes affected

PYGL (HGNC:9725): (glycogen phosphorylase L) This gene encodes a homodimeric protein that catalyses the cleavage of alpha-1,4-glucosidic bonds to release glucose-1-phosphate from liver glycogen stores. This protein switches from inactive phosphorylase B to active phosphorylase A by phosphorylation of serine residue 15. Activity of this enzyme is further regulated by multiple allosteric effectors and hormonal controls. Humans have three glycogen phosphorylase genes that encode distinct isozymes that are primarily expressed in liver, brain and muscle, respectively. The liver isozyme serves the glycemic demands of the body in general while the brain and muscle isozymes supply just those tissues. In glycogen storage disease type VI, also known as Hers disease, mutations in liver glycogen phosphorylase inhibit the conversion of glycogen to glucose and results in moderate hypoglycemia, mild ketosis, growth retardation and hepatomegaly. Alternative splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Feb 2011]

PYGL Gene-Disease associations (from GenCC):

• glycogen storage disease VI

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 13: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.098901).
• BP6: Variant 14-50915919-G-A is Benign according to our data. Variant chr14-50915919-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 522775.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00426 (649/152360) while in subpopulation NFE AF = 0.00757 (515/68036). AF 95% confidence interval is 0.00703. There are 4 homozygotes in GnomAd4. There are 290 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002863.5. 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
	PYGL	NM_002863.5	MANE Select	c.1145C>T	p.Pro382Leu	missense	Exon 10 of 20	NP_002854.3
	PYGL	NM_001163940.2		c.1043C>T	p.Pro348Leu	missense	Exon 9 of 19	NP_001157412.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGL	ENST00000216392.8	TSL:1 MANE Select	c.1145C>T	p.Pro382Leu	missense	Exon 10 of 20	ENSP00000216392.7
	PYGL	ENST00000532462.5	TSL:1	c.1145C>T	p.Pro382Leu	missense	Exon 10 of 20	ENSP00000431657.1
	PYGL	ENST00000874287.1		c.1160C>T	p.Pro387Leu	missense	Exon 10 of 20	ENSP00000544346.1

Frequencies

GnomAD3 genomes AF: 0.00426 AC: 649 AN: 152242 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00757

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00411 AC: 1032 AN: 251388 AF XY: 0.00424

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00277

Gnomad NFE exome AF: 0.00724

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00559 AC: 8175 AN: 1461854 Hom.: 31 Cov.: 32 AF XY: 0.00554 AC XY: 4028 AN XY: 727224

African (AFR) AF: 0.00108 AC: 36 AN: 33480

American (AMR) AF: 0.00130 AC: 58 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 33 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00158 AC: 136 AN: 86256

European-Finnish (FIN) AF: 0.00333 AC: 178 AN: 53406

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00672 AC: 7477 AN: 1111990

Other (OTH) AF: 0.00412 AC: 249 AN: 60394

GnomAD4 genome AF: 0.00426 AC: 649 AN: 152360 Hom.: 4 Cov.: 33 AF XY: 0.00389 AC XY: 290 AN XY: 74506

African (AFR) AF: 0.00120 AC: 50 AN: 41576

American (AMR) AF: 0.00170 AC: 26 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4832

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00757 AC: 515 AN: 68036

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00630 Hom.: 14

Bravo AF: 0.00408

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.00455 AC: 552

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	6	3	Glycogen storage disease, type VI (9)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	PYGL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.099	T
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		10
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MVP		1.0
MPC		0.55
ClinPred		0.17	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.95
Mutation Taster		=14/86	disease causing

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: rs143759519; hg19: chr14-51382637; COSMIC: COSV53588315; COSMIC: COSV53588315;