rs140375476

chr1-99876507-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000642.3(AGL):c.1333A>G(p.Met445Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000478 in 1,611,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.464

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.028521895).
• BP6: Variant 1-99876507-A-G is Benign according to our data. Variant chr1-99876507-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 526590.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGL	NM_000642.3	c.1333A>G	p.Met445Val	missense_variant	11/34	ENST00000361915.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGL	ENST00000361915.8	c.1333A>G	p.Met445Val	missense_variant	11/34	1	NM_000642.3	P1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000717 AC: 18 AN: 251096 Hom.: 0 AF XY: 0.0000663 AC XY: 9 AN XY: 135700

Gnomad AFR exome AF: 0.000924

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000247 AC: 36 AN: 1459396 Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 16 AN XY: 726144

Gnomad4 AFR exome AF: 0.000748

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000541

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74374

Gnomad4 AFR AF: 0.000941

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000330 Hom.: 0

Bravo AF: 0.000329

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glycogen storage disease type III Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2019	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

May 23, 2023

BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	14
Dann	Benign	0.59
DEOGEN2	Benign	0.028	T;T;T;T;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.63	T;.;.;.;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.029	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.0	L;L;L;L;.
MutationTaster	Benign	0.99	N;N;N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.080	N;N;N;N;N
REVEL	Benign	0.098
Sift	Benign	0.52	T;T;T;T;T
Sift4G	Benign	0.64	T;T;T;T;T
Polyphen		0.0	B;B;B;B;B
Vest4		0.33
MVP		0.60
MPC		0.041
ClinPred		0.0019	T
GERP RS		0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.038
gMVP		0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs140375476; hg19: chr1-100342063;