rs17121403

Variant names:

• chr1-99870421-A-G
• rs17121403
• NM_000642.3:c.686A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000642.3(AGL):​c.686A>G​(p.Gln229Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0242 in 1,613,906 control chromosomes in the GnomAD database, including 969 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (259 hom., cov: 32)
  • Exomes 𝑓: 0.022 (710 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.68
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• glycogen storage disease III

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018741786).
• BP6: Variant 1-99870421-A-G is Benign according to our data. Variant chr1-99870421-A-G is described in ClinVar as Benign. ClinVar VariationId is 256749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0934 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000642.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	NM_000642.3	MANE Select	c.686A>G	p.Gln229Arg	missense	Exon 6 of 34	NP_000633.2	P35573-1
	AGL	NM_000028.3		c.686A>G	p.Gln229Arg	missense	Exon 6 of 34	NP_000019.2	P35573-1
	AGL	NM_000643.3		c.686A>G	p.Gln229Arg	missense	Exon 6 of 34	NP_000634.2	A0A0S2A4E4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	ENST00000361915.8	TSL:1 MANE Select	c.686A>G	p.Gln229Arg	missense	Exon 6 of 34	ENSP00000355106.3	P35573-1
	AGL	ENST00000294724.8	TSL:1	c.686A>G	p.Gln229Arg	missense	Exon 6 of 34	ENSP00000294724.4	P35573-1
	AGL	ENST00000370163.7	TSL:1	c.686A>G	p.Gln229Arg	missense	Exon 6 of 34	ENSP00000359182.3	P35573-1

Frequencies

GnomAD3 genomes AF: 0.0426 AC: 6475 AN: 152160 Hom.: 250 Cov.: 32

Gnomad AFR AF: 0.0953

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0599

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.0333

Gnomad SAS AF: 0.0192

Gnomad FIN AF: 0.00461

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0416

GnomAD2 exomes AF: 0.0338 AC: 8504 AN: 251232 AF XY: 0.0291

Gnomad AFR exome AF: 0.0945

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.00715

Gnomad EAS exome AF: 0.0269

Gnomad FIN exome AF: 0.00582

Gnomad NFE exome AF: 0.0165

Gnomad OTH exome AF: 0.0256

GnomAD4 exome AF: 0.0222 AC: 32486 AN: 1461628 Hom.: 710 Cov.: 32 AF XY: 0.0213 AC XY: 15520 AN XY: 727134

African (AFR) AF: 0.0968 AC: 3238 AN: 33466

American (AMR) AF: 0.0985 AC: 4406 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00781 AC: 204 AN: 26130

East Asian (EAS) AF: 0.0389 AC: 1543 AN: 39658

South Asian (SAS) AF: 0.0205 AC: 1771 AN: 86250

European-Finnish (FIN) AF: 0.00646 AC: 345 AN: 53414

Middle Eastern (MID) AF: 0.0101 AC: 58 AN: 5766

European-Non Finnish (NFE) AF: 0.0176 AC: 19515 AN: 1111838

Other (OTH) AF: 0.0233 AC: 1406 AN: 60384

GnomAD4 genome AF: 0.0428 AC: 6513 AN: 152278 Hom.: 259 Cov.: 32 AF XY: 0.0430 AC XY: 3199 AN XY: 74462

African (AFR) AF: 0.0959 AC: 3983 AN: 41546

American (AMR) AF: 0.0601 AC: 918 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3472

East Asian (EAS) AF: 0.0334 AC: 173 AN: 5182

South Asian (SAS) AF: 0.0190 AC: 92 AN: 4834

European-Finnish (FIN) AF: 0.00461 AC: 49 AN: 10622

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0168 AC: 1141 AN: 68020

Other (OTH) AF: 0.0412 AC: 87 AN: 2112

Alfa AF: 0.0278 Hom.: 362

Bravo AF: 0.0511

TwinsUK AF: 0.0194 AC: 72

ALSPAC AF: 0.0184 AC: 71

ESP6500AA AF: 0.0876 AC: 386

ESP6500EA AF: 0.0188 AC: 162

ExAC AF: 0.0326 AC: 3953

Asia WGS AF: 0.0350 AC: 121 AN: 3476

EpiCase AF: 0.0168

EpiControl AF: 0.0164

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Glycogen storage disease type III (5)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Benign	0.70
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.71	N
PhyloP100		1.7
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.12
Sift	Benign	0.86	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.043
MPC		0.043
ClinPred		0.0016	T
GERP RS		4.2
Varity_R		0.039
gMVP		0.59
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17121403; hg19: chr1-100335977; COSMIC: COSV108107724; COSMIC: COSV108107724;