NM_000642.3:c.1424-44A>G

Variant names:

• chr1-99877597-A-G
• rs2291638
• NM_000642.3:c.1424-44A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000642.3(AGL):​c.1424-44A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 1,577,868 control chromosomes in the GnomAD database, including 113,843 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8133 hom., cov: 32)
  • Exomes 𝑓: 0.38 (105710 hom.)
• Consequence: AGL NM_000642.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.558
• Publications: 6 publications found

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]

AGL Gene-Disease associations (from GenCC):

• glycogen storage disease III

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Laboratory for Molecular Medicine, Myriad Women’s Health, Orphanet, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-99877597-A-G is Benign according to our data. Variant chr1-99877597-A-G is described in ClinVar as Benign. ClinVar VariationId is 256722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGL	NM_000642.3	c.1424-44A>G		intron_variant	Intron 11 of 33	ENST00000361915.8	NP_000633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8	c.1424-44A>G		intron_variant	Intron 11 of 33	1	NM_000642.3	ENSP00000355106.3

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45120 AN: 151976 Hom.: 8120 Cov.: 32

Gnomad AFR AF: 0.0932

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.460

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.346

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.393

Gnomad OTH AF: 0.317

GnomAD2 exomes AF: 0.351 AC: 86835 AN: 247060 AF XY: 0.352

Gnomad AFR exome AF: 0.0899

Gnomad AMR exome AF: 0.360

Gnomad ASJ exome AF: 0.301

Gnomad EAS exome AF: 0.445

Gnomad FIN exome AF: 0.345

Gnomad NFE exome AF: 0.388

Gnomad OTH exome AF: 0.363

GnomAD4 exome AF: 0.379 AC: 540994 AN: 1425774 Hom.: 105710 Cov.: 25 AF XY: 0.377 AC XY: 268273 AN XY: 711422

African (AFR) AF: 0.0817 AC: 2667 AN: 32660

American (AMR) AF: 0.355 AC: 15805 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 8058 AN: 25920

East Asian (EAS) AF: 0.461 AC: 18176 AN: 39440

South Asian (SAS) AF: 0.305 AC: 26078 AN: 85454

European-Finnish (FIN) AF: 0.353 AC: 18537 AN: 52532

Middle Eastern (MID) AF: 0.229 AC: 1307 AN: 5714

European-Non Finnish (NFE) AF: 0.397 AC: 429114 AN: 1080374

Other (OTH) AF: 0.359 AC: 21252 AN: 59140

GnomAD4 genome AF: 0.297 AC: 45152 AN: 152094 Hom.: 8133 Cov.: 32 AF XY: 0.296 AC XY: 21987 AN XY: 74330

African (AFR) AF: 0.0932 AC: 3869 AN: 41528

American (AMR) AF: 0.324 AC: 4957 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 1037 AN: 3472

East Asian (EAS) AF: 0.459 AC: 2377 AN: 5174

South Asian (SAS) AF: 0.311 AC: 1498 AN: 4816

European-Finnish (FIN) AF: 0.346 AC: 3658 AN: 10558

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.393 AC: 26696 AN: 67938

Other (OTH) AF: 0.325 AC: 686 AN: 2112

Alfa AF: 0.342 Hom.: 1812

Bravo AF: 0.290

Asia WGS AF: 0.366 AC: 1274 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glycogen storage disease type III Benign:1

Jul 14, 2021

Genome-Nilou Lab

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	-0.68
CADD	Benign	9.1
DANN	Benign	0.85
PhyloP100		-0.56
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2291638; hg19: chr1-100343153; COSMIC: COSV54049682; COSMIC: COSV54049682;