rs146041189

Positions:

• chr1-99880781-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_000642.3(AGL):​c.1885G>A​(p.Glu629Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,613,954 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E629D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 9.53

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]

AGL (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04611823).
• BP6: Variant 1-99880781-G-A is Benign according to our data. Variant chr1-99880781-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289630.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00149 (227/152292) while in subpopulation AFR AF= 0.0051 (212/41560). AF 95% confidence interval is 0.00454. There are 0 homozygotes in gnomad4. There are 110 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGL	NM_000642.3	c.1885G>A	p.Glu629Lys	missense_variant	14/34	ENST00000361915.8	NP_000633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8	c.1885G>A	p.Glu629Lys	missense_variant	14/34	1	NM_000642.3	ENSP00000355106.3

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 228 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00514

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.00287

GnomAD3 exomes AF: 0.000370 AC: 93 AN: 251304 Hom.: 0 AF XY: 0.000221 AC XY: 30 AN XY: 135808

Gnomad AFR exome AF: 0.00529

Gnomad AMR exome AF: 0.000116

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: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000123 AC: 180 AN: 1461662 Hom.: 0 Cov.: 31 AF XY: 0.000106 AC XY: 77 AN XY: 727136

Gnomad4 AFR exome AF: 0.00433

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.00149 AC: 227 AN: 152292 Hom.: 0 Cov.: 33 AF XY: 0.00148 AC XY: 110 AN XY: 74462

Gnomad4 AFR AF: 0.00510

Gnomad4 AMR AF: 0.000588

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: 0.00284

Alfa AF: 0.000292 Hom.: 0

Bravo AF: 0.00161

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000527 AC: 64

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 30, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 10, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 28, 2023	The AGL c.1885G>A; p.Glu629Lys variant (rs146041189), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 289630). This variant is observed in the general population with an overall allele frequency of 0.05% (146/282700 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.646). Due to limited information, the clinical significance of this variant is uncertain at this time. -

Glycogen storage disease type III Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

AGL-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 03, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T;T;T;T;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;.;.;D
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.046	T;T;T;T;T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	3.0	M;M;M;M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.5	N;N;N;N;N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.019	D;D;D;D;D
Sift4G	Uncertain	0.044	D;D;D;D;T
Polyphen		0.95	P;P;P;P;D
Vest4		0.92
MVP		0.94
MPC		0.24
ClinPred		0.083	T
GERP RS		6.1
Varity_R		0.46
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs146041189; hg19: chr1-100346337;