1-99891337-G-T

Variant names:

• chr1-99891337-G-T
• rs147977213
• NM_000642.3:c.2930G>T
• AGL p.Arg977Leu

Variant summary

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

The NM_000642.3(AGL):​c.2930G>T​(p.Arg977Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,436 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R977Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.14
• 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: Laboratory for Molecular Medicine, Myriad Women's Health, Genomics England PanelApp, G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.2930G>T	p.Arg977Leu	missense	Exon 22 of 34	NP_000633.2	P35573-1
	AGL	NM_000028.3		c.2930G>T	p.Arg977Leu	missense	Exon 22 of 34	NP_000019.2	P35573-1
	AGL	NM_000643.3		c.2930G>T	p.Arg977Leu	missense	Exon 22 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.2930G>T	p.Arg977Leu	missense	Exon 22 of 34	ENSP00000355106.3	P35573-1
	AGL	ENST00000294724.8	TSL:1	c.2930G>T	p.Arg977Leu	missense	Exon 22 of 34	ENSP00000294724.4	P35573-1
	AGL	ENST00000370163.7	TSL:1	c.2930G>T	p.Arg977Leu	missense	Exon 22 of 34	ENSP00000359182.3	P35573-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000438 AC: 11 AN: 251052 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461436 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 726994

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.000428 AC: 17 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111726

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	Glycogen storage disease type III (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.48
Sift	Benign	0.59	T
Sift4G	Benign	0.61	T
Varity_R		0.54
gMVP		0.73
Mutation Taster		=53/47	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs147977213;

hg19: chr1-100356893;