rs555408487

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000216392.8(PYGL):​c.2110G>A​(p.Ala704Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A704A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

PYGL
ENST00000216392.8 missense

Scores

11
5
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.88
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.79

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PYGLNM_002863.5 linkuse as main transcriptc.2110G>A p.Ala704Thr missense_variant 17/20 ENST00000216392.8 NP_002854.3
PYGLNM_001163940.2 linkuse as main transcriptc.2008G>A p.Ala670Thr missense_variant 16/19 NP_001157412.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PYGLENST00000216392.8 linkuse as main transcriptc.2110G>A p.Ala704Thr missense_variant 17/201 NM_002863.5 ENSP00000216392 P1P06737-1
PYGLENST00000532462.5 linkuse as main transcriptc.2110G>A p.Ala704Thr missense_variant 17/201 ENSP00000431657
PYGLENST00000544180.6 linkuse as main transcriptc.2008G>A p.Ala670Thr missense_variant 16/192 ENSP00000443787 P06737-2
PYGLENST00000532107.2 linkuse as main transcriptn.283G>A non_coding_transcript_exon_variant 2/45

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152220
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251472
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000889
AC:
13
AN:
1461884
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152338
Hom.:
0
Cov.:
32
AF XY:
0.0000268
AC XY:
2
AN XY:
74492
show subpopulations
Gnomad4 AFR
AF:
0.0000962
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000340
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Glycogen storage disease, type VI Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 11, 2018This variant has not been reported in the literature in individuals with PYGL-related disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 704 of the PYGL protein (p.Ala704Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Pathogenic
0.22
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.49
.;.;T
Eigen
Pathogenic
0.69
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Uncertain
0.24
D
MetaRNN
Pathogenic
0.79
D;D;D
MetaSVM
Pathogenic
0.84
D
MutationAssessor
Pathogenic
3.0
.;.;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Benign
-1.4
N;N;N
REVEL
Pathogenic
0.79
Sift
Uncertain
0.0050
D;D;D
Sift4G
Uncertain
0.0030
D;D;D
Polyphen
0.89
.;.;P
Vest4
0.74
MutPred
0.67
Loss of helix (P = 0.1299);.;Loss of helix (P = 0.1299);
MVP
0.97
MPC
0.53
ClinPred
0.88
D
GERP RS
5.9
Varity_R
0.82
gMVP
0.80

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs555408487; hg19: chr14-51376680; API