rs17121464

chr1-99875231-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000642.3(AGL):c.1160G>A(p.Arg387Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,613,966 control chromosomes in the GnomAD database, including 2,309 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (219 hom., cov: 33)
  • Exomes 𝑓: 0.019 (2090 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.70

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013240874).
• BP6: Variant 1-99875231-G-A is Benign according to our data. Variant chr1-99875231-G-A is described in ClinVar as [Benign]. Clinvar id is 199034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-99875231-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGL	NM_000642.3	c.1160G>A	p.Arg387Gln	missense_variant	9/34	ENST00000361915.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGL	ENST00000361915.8	c.1160G>A	p.Arg387Gln	missense_variant	9/34	1	NM_000642.3	P1

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 3162 AN: 152160 Hom.: 217 Cov.: 33

Gnomad AFR AF: 0.00357

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0712

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.0116

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00250

Gnomad OTH AF: 0.0306

GnomAD3 exomes AF: 0.0524 AC: 13144 AN: 250642 Hom.: 1085 AF XY: 0.0502 AC XY: 6808 AN XY: 135718

Gnomad AFR exome AF: 0.00340

Gnomad AMR exome AF: 0.165

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.177

Gnomad SAS exome AF: 0.112

Gnomad FIN exome AF: 0.0100

Gnomad NFE exome AF: 0.00190

Gnomad OTH exome AF: 0.0366

GnomAD4 exome AF: 0.0187 AC: 27344 AN: 1461688 Hom.: 2090 Cov.: 32 AF XY: 0.0207 AC XY: 15056 AN XY: 727164

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.154

Gnomad4 ASJ exome AF: 0.00486

Gnomad4 EAS exome AF: 0.185

Gnomad4 SAS exome AF: 0.110

Gnomad4 FIN exome AF: 0.0106

Gnomad4 NFE exome AF: 0.00126

Gnomad4 OTH exome AF: 0.0233

GnomAD4 genome AF: 0.0209 AC: 3176 AN: 152278 Hom.: 219 Cov.: 33 AF XY: 0.0245 AC XY: 1823 AN XY: 74450

Gnomad4 AFR AF: 0.00356

Gnomad4 AMR AF: 0.0717

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.184

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.0116

Gnomad4 NFE AF: 0.00250

Gnomad4 OTH AF: 0.0326

Alfa AF: 0.0118 Hom.: 273

Bravo AF: 0.0266

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.0474 AC: 5752

Asia WGS AF: 0.143 AC: 500 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00178

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease type III Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Oct 26, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	8.9
Dann	Benign	0.37
DEOGEN2	Benign	0.033	T;T;T;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.52	T;.;.;.;T
MetaRNN	Benign	0.0013	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;L;L;L;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.29	N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.85	T;T;T;T;T
Sift4G	Benign	0.59	T;T;T;T;T
Polyphen		0.0	B;B;B;B;B
Vest4		0.051
MPC		0.045
ClinPred		0.0015	T
GERP RS		-2.4
Varity_R		0.021
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs17121464; hg19: chr1-100340787; COSMIC: COSV54048998;