rs200129247

Positions:

• chr1-99891682-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000642.3(AGL):​c.3026C>T​(p.Ala1009Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000521 in 1,613,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 7.53

Genes affected

AGL (HGNC:321): (amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase) This gene encodes the glycogen debrancher enzyme which is involved in glycogen degradation. This enzyme has two independent catalytic activities which occur at different sites on the protein: a 4-alpha-glucotransferase activity and a amylo-1,6-glucosidase activity. Mutations in this gene are associated with glycogen storage disease although a wide range of enzymatic and clinical variability occurs which may be due to tissue-specific alternative splicing. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25806278).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGL	NM_000642.3	c.3026C>T	p.Ala1009Val	missense_variant	23/34	ENST00000361915.8	NP_000633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8	c.3026C>T	p.Ala1009Val	missense_variant	23/34	1	NM_000642.3	ENSP00000355106	P1

Frequencies

GnomAD3 genomes AF: 0.0000724 AC: 11 AN: 152038 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000995 AC: 25 AN: 251308 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135824

Gnomad AFR exome AF: 0.00

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: 0.00111

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000500 AC: 73 AN: 1461248 Hom.: 0 Cov.: 33 AF XY: 0.0000495 AC XY: 36 AN XY: 726952

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00135

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000724 AC: 11 AN: 152038 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74256

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000944

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000181 Hom.: 0

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Glycogen storage disease type III Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 20, 2022	Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. ClinVar contains an entry for this variant (Variation ID: 456481). This variant has not been reported in the literature in individuals affected with AGL-related conditions. This variant is present in population databases (rs200129247, gnomAD 0.1%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1009 of the AGL protein (p.Ala1009Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	23
DANN	Benign	0.80
DEOGEN2	Benign	0.072	T;T;T;T;.
Eigen	Benign	-0.058
Eigen_PC	Benign	0.072
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;.;.;.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.9	L;L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.14	N;N;N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.77	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.21	B;B;B;B;B
Vest4		0.78
MutPred		0.43		Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);.;
MVP		0.79
MPC		0.061
ClinPred		0.19	T
GERP RS		5.6
Varity_R		0.18
gMVP		0.61

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

Other links and lift over

dbSNP: rs200129247; hg19: chr1-100357238;