rs28730706

chr1-99912417-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000642.3(AGL):c.3849T>C(p.Ala1283=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,613,776 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (27 hom., cov: 33)
  • Exomes 𝑓: 0.013 (167 hom.)
• Consequence: AGL NM_000642.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.28

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 1-99912417-T-C is Benign according to our data. Variant chr1-99912417-T-C is described in ClinVar as [Benign]. Clinvar id is 256745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-99912417-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.28 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0131 (2001/152334) while in subpopulation NFE AF= 0.0162 (1099/68032). AF 95% confidence interval is 0.0154. There are 27 homozygotes in gnomad4. There are 1008 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGL	NM_000642.3	c.3849T>C	p.Ala1283=	synonymous_variant	29/34	ENST00000361915.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGL	ENST00000361915.8	c.3849T>C	p.Ala1283=	synonymous_variant	29/34	1	NM_000642.3	P1

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2004 AN: 152216 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.00260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.0363

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.0210

GnomAD3 exomes AF: 0.0137 AC: 3452 AN: 251234 Hom.: 38 AF XY: 0.0138 AC XY: 1874 AN XY: 135786

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00649

Gnomad ASJ exome AF: 0.0284

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00392

Gnomad FIN exome AF: 0.0344

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.0194

GnomAD4 exome AF: 0.0132 AC: 19328 AN: 1461442 Hom.: 167 Cov.: 30 AF XY: 0.0133 AC XY: 9652 AN XY: 727032

Gnomad4 AFR exome AF: 0.00302

Gnomad4 AMR exome AF: 0.00738

Gnomad4 ASJ exome AF: 0.0290

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00451

Gnomad4 FIN exome AF: 0.0348

Gnomad4 NFE exome AF: 0.0133

Gnomad4 OTH exome AF: 0.0148

GnomAD4 genome AF: 0.0131 AC: 2001 AN: 152334 Hom.: 27 Cov.: 33 AF XY: 0.0135 AC XY: 1008 AN XY: 74490

Gnomad4 AFR AF: 0.00260

Gnomad4 AMR AF: 0.0141

Gnomad4 ASJ AF: 0.0294

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.0363

Gnomad4 NFE AF: 0.0162

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.0168 Hom.: 15

Bravo AF: 0.0104

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0172

EpiControl AF: 0.0167

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease type III Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 31, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 14, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	9.0
Dann	Benign	0.61
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: rs28730706; hg19: chr1-100377973;