rs794729209

Positions:

• chr1-99875455-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The ENST00000361915.8(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 ENST00000361915.8 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.41

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 Uncertain_significance. Variant got 4 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 id is 265998.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8	c.1283G>A	p.Arg428Lys	missense_variant, splice_region_variant	10/34	1	NM_000642.3	ENSP00000355106	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs794729209; hg19: chr1-100341011;