rs143885684

chr1-99910833-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 2P and 15B. PM2 BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_000642.3(AGL):c.3822C>T(p.Ile1274=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000093 in 1,612,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: AGL NM_000642.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.620

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 Benign. Variant got -13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 1-99910833-C-T is Benign according to our data. Variant chr1-99910833-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 384995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.62 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00048 (73/152180) while in subpopulation AFR AF= 0.00168 (70/41544). AF 95% confidence interval is 0.00137. There are 0 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGL	NM_000642.3	c.3822C>T	p.Ile1274=	synonymous_variant	28/34	ENST00000361915.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGL	ENST00000361915.8	c.3822C>T	p.Ile1274=	synonymous_variant	28/34	1	NM_000642.3	P1

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152066 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000116 AC: 29 AN: 250304 Hom.: 0 AF XY: 0.0000591 AC XY: 8 AN XY: 135272

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000527 AC: 77 AN: 1460596 Hom.: 0 Cov.: 30 AF XY: 0.0000633 AC XY: 46 AN XY: 726576

Gnomad4 AFR exome AF: 0.00200

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.000480 AC: 73 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74410

Gnomad4 AFR AF: 0.00168

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000747 Hom.: 0

Bravo AF: 0.000665

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease type III Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
Cadd	Benign	7.1
Dann	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs143885684; hg19: chr1-100376389; COSMIC: COSV104592651;