Genetic Variant PYGL:p.Tyr204Phe (chr14-50924018-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002863.5(PYGL):c.611A>T(p.Tyr204Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y204C) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

PYGL
NM_002863.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.28

Publications

0 publications found

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]

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

PYGL links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGL	NM_002863.5 link	c.611A>T	p.Tyr204Phe	missense_variant	Exon 5 of 20	ENST00000216392.8	NP_002854.3
PYGL	NM_001163940.2 link	c.509A>T	p.Tyr170Phe	missense_variant	Exon 4 of 19		NP_001157412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PYGL	ENST00000216392.8 link	c.611A>T	p.Tyr204Phe	missense_variant	Exon 5 of 20	1	NM_002863.5	ENSP00000216392.7
PYGL	ENST00000532462.5 link	c.611A>T	p.Tyr204Phe	missense_variant	Exon 5 of 20	1		ENSP00000431657.1
PYGL	ENST00000530336.2 link	n.678A>T		non_coding_transcript_exon_variant	Exon 5 of 5	1
PYGL	ENST00000544180.6 link	c.509A>T	p.Tyr170Phe	missense_variant	Exon 4 of 19	2		ENSP00000443787.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.56

.;.;D

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.063

MetaRNN

Uncertain

0.68

D;D;D

MetaSVM

Uncertain

0.41

MutationAssessor

Benign

1.7

.;.;L

PhyloP100

6.3

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.1

D;D;D

REVEL

Uncertain

0.56

Sift

Benign

0.16

T;T;T

Sift4G

Benign

0.35

T;T;T

Polyphen

0.038

B;.;B

Vest4

0.66

MutPred

0.64

Gain of methylation at K206 (P = 0.0443);.;Gain of methylation at K206 (P = 0.0443);

MVP

0.93

MPC

0.52

ClinPred

0.94

GERP RS

6.2

Varity_R

0.61

gMVP

0.71

Mutation Taster

=20/80

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over