chr1-99884597-G-T

Variant names:

• chr1-99884597-G-T
• rs773083396
• NM_000642.3:c.2575G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000028.3(AGL):​c.2575G>T​(p.Ala859Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A859T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AGL NM_000028.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.87
• 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: 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20596021).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000028.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	NM_000642.3	MANE Select	c.2575G>T	p.Ala859Ser	missense	Exon 20 of 34	NP_000633.2
	AGL	NM_000028.3		c.2575G>T	p.Ala859Ser	missense	Exon 20 of 34	NP_000019.2
	AGL	NM_000643.3		c.2575G>T	p.Ala859Ser	missense	Exon 20 of 34	NP_000634.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	ENST00000361915.8	TSL:1 MANE Select	c.2575G>T	p.Ala859Ser	missense	Exon 20 of 34	ENSP00000355106.3
	AGL	ENST00000294724.8	TSL:1	c.2575G>T	p.Ala859Ser	missense	Exon 20 of 34	ENSP00000294724.4
	AGL	ENST00000370163.7	TSL:1	c.2575G>T	p.Ala859Ser	missense	Exon 20 of 34	ENSP00000359182.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Glycogen storage disease type III (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.86	L
PhyloP100		3.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.074
Sift	Benign	0.36	T
Sift4G	Benign	0.69	T
Polyphen		0.10	B
Vest4		0.49
MutPred		0.54		Loss of helix (P = 0.028)
MVP		0.43
MPC		0.045
ClinPred		0.66	D
GERP RS		5.7
Varity_R		0.12
gMVP		0.50
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs773083396; hg19: chr1-100350153;