rs375755924

chr1-99915416-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_000642.3(AGL):c.4189G>A(p.Ala1397Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,613,802 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000065 (1 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 9.46

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]

LOC124904230 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000592 (9/152086) while in subpopulation SAS AF= 0.00187 (9/4814). AF 95% confidence interval is 0.000975. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGL	NM_000642.3	c.4189G>A	p.Ala1397Thr	missense_variant	31/34	ENST00000361915.8
LOC124904230	XR_007066249.1	n.1146-2199C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGL	ENST00000361915.8	c.4189G>A	p.Ala1397Thr	missense_variant	31/34	1	NM_000642.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 151968 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000155 AC: 39 AN: 251112 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000650 AC: 95 AN: 1461716 Hom.: 1 Cov.: 31 AF XY: 0.0000894 AC XY: 65 AN XY: 727152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000997

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000278 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.000173 AC: 21

Asia WGS AF: 0.000867 AC: 3 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glycogen storage disease type III Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 21, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	- -
Uncertain significance, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.36	T;T;T;T;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;.;.;.;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.57	D;D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	4.0	H;H;H;H;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.95
MutPred		0.81		Loss of catalytic residue at A1397 (P = 0.0222);Loss of catalytic residue at A1397 (P = 0.0222);Loss of catalytic residue at A1397 (P = 0.0222);Loss of catalytic residue at A1397 (P = 0.0222);.;
MVP		0.94
MPC		0.29
ClinPred		0.67	D
GERP RS		5.8
Varity_R		0.76
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs375755924; hg19: chr1-100380972;