rs794729209

Variant names:

• chr1-99875455-G-A
• rs794729209
• NM_000642.3:c.1283G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000642.3(AGL):​c.1283G>A​(p.Arg428Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as no classification for the single variant (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R428G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AGL NM_000642.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.41
• Publications: 3 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: ClinGen, Ambry Genetics, Laboratory for Molecular Medicine, Myriad Women’s Health, Orphanet, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-99875454-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 265998.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGL	NM_000642.3	c.1283G>A	p.Arg428Lys	missense_variant, splice_region_variant	Exon 10 of 34	ENST00000361915.8	NP_000633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8	c.1283G>A	p.Arg428Lys	missense_variant, splice_region_variant	Exon 10 of 34	1	NM_000642.3	ENSP00000355106.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Benign	0.89
DEOGEN2	Benign	0.049	T;T;T;T;.
Eigen	Benign	0.035
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;.;.;.;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.39	T;T;T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.6	L;L;L;L;.
PhyloP100		6.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.93	N;N;N;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.58	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.015	B;B;B;B;B
Vest4		0.39
MutPred		0.78		Gain of methylation at R428 (P = 0.0076);Gain of methylation at R428 (P = 0.0076);Gain of methylation at R428 (P = 0.0076);Gain of methylation at R428 (P = 0.0076);.;
MVP		0.82
MPC		0.042
ClinPred		0.49	T
GERP RS		5.9
Varity_R		0.37
gMVP		0.69
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.72		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs794729209; hg19: chr1-100341011;