rs140333425

Variant names:

• chr1-99896267-G-A
• rs140333425
• NM_000642.3:c.3260-19G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000642.3(AGL):​c.3260-19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,568,336 control chromosomes in the GnomAD database, including 187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (28 hom., cov: 32)
  • Exomes 𝑓: 0.013 (159 hom.)
• Consequence: AGL NM_000642.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.19

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 1-99896267-G-A is Benign according to our data. Variant chr1-99896267-G-A is described in ClinVar as [Benign]. Clinvar id is 256736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0128 (1951/152212) while in subpopulation NFE AF= 0.0155 (1052/68004). AF 95% confidence interval is 0.0147. There are 28 homozygotes in gnomad4. There are 989 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGL	NM_000642.3	c.3260-19G>A		intron_variant	Intron 24 of 33	ENST00000361915.8	NP_000633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8	c.3260-19G>A		intron_variant	Intron 24 of 33	1	NM_000642.3	ENSP00000355106.3

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1953 AN: 152094 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0366

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0155

Gnomad OTH AF: 0.0211

GnomAD3 exomes AF: 0.0135 AC: 3401 AN: 251388 Hom.: 36 AF XY: 0.0136 AC XY: 1846 AN XY: 135870

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.00648

Gnomad ASJ exome AF: 0.0285

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00363

Gnomad FIN exome AF: 0.0343

Gnomad NFE exome AF: 0.0166

Gnomad OTH exome AF: 0.0194

GnomAD4 exome AF: 0.0127 AC: 17917 AN: 1416124 Hom.: 159 Cov.: 26 AF XY: 0.0127 AC XY: 9015 AN XY: 707360

Gnomad4 AFR exome AF: 0.00287

Gnomad4 AMR exome AF: 0.00737

Gnomad4 ASJ exome AF: 0.0288

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00422

Gnomad4 FIN exome AF: 0.0348

Gnomad4 NFE exome AF: 0.0125

Gnomad4 OTH exome AF: 0.0143

GnomAD4 genome AF: 0.0128 AC: 1951 AN: 152212 Hom.: 28 Cov.: 32 AF XY: 0.0133 AC XY: 989 AN XY: 74414

Gnomad4 AFR AF: 0.00243

Gnomad4 AMR AF: 0.0142

Gnomad4 ASJ AF: 0.0294

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.0366

Gnomad4 NFE AF: 0.0155

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.0194 Hom.: 12

Bravo AF: 0.0102

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 14, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 31, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

Feb 10, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glycogen storage disease type III Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.2
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs140333425; hg19: chr1-100361823;