1-99900819-G-T

Variant names:

• chr1-99900819-G-T
• rs758562610
• NM_000642.3:c.3546G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000642.3(AGL):​c.3546G>T​(p.Met1182Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000378 in 1,613,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 5.70
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3167412).

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.3546G>T	p.Met1182Ile	missense	Exon 26 of 34	NP_000633.2	P35573-1
	AGL	NM_000028.3		c.3546G>T	p.Met1182Ile	missense	Exon 26 of 34	NP_000019.2	P35573-1
	AGL	NM_000643.3		c.3546G>T	p.Met1182Ile	missense	Exon 26 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.3546G>T	p.Met1182Ile	missense	Exon 26 of 34	ENSP00000355106.3	P35573-1
	AGL	ENST00000294724.8	TSL:1	c.3546G>T	p.Met1182Ile	missense	Exon 26 of 34	ENSP00000294724.4	P35573-1
	AGL	ENST00000370163.7	TSL:1	c.3546G>T	p.Met1182Ile	missense	Exon 26 of 34	ENSP00000359182.3	P35573-1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151616 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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251480 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1461454 Hom.: 0 Cov.: 32 AF XY: 0.0000426 AC XY: 31 AN XY: 727074

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.0000447 AC: 2 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1111666

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151616 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 73986

African (AFR) AF: 0.00 AC: 0 AN: 41240

American (AMR) AF: 0.00 AC: 0 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000564 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	-	Glycogen storage disease type III (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Benign	0.68
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.034
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.57	N
PhyloP100		5.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.089
Sift	Benign	1.0	T
Sift4G	Benign	0.98	T
Polyphen		0.0030	B
Vest4		0.59
MutPred		0.50		Gain of catalytic residue at P1184 (P = 0.03)
MVP		0.69
MPC		0.046
ClinPred		0.18	T
GERP RS		4.7
Varity_R		0.21
gMVP		0.57
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs758562610; hg19: chr1-100366375;