rs2274570

Variant names:

• chr1-99910892-G-A
• rs2274570
• NM_000642.3:c.3836+45G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-99910892-G-A
• chr1-99910892-G-T

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.3836+45G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 1,582,054 control chromosomes in the GnomAD database, including 199,900 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16725 hom., cov: 31)
  • Exomes 𝑓: 0.50 (183175 hom.)
• Consequence: AGL NM_000642.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.294
• Publications: 9 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=-0.92).
• BP6: Variant 1-99910892-G-A is Benign according to our data. Variant chr1-99910892-G-A is described in ClinVar as Benign. ClinVar VariationId is 256744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.552 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000642.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	NM_000642.3	MANE Select	c.3836+45G>A		intron	N/A	NP_000633.2
	AGL	NM_000028.3		c.3836+45G>A		intron	N/A	NP_000019.2
	AGL	NM_000643.3		c.3836+45G>A		intron	N/A	NP_000634.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	ENST00000361915.8	TSL:1 MANE Select	c.3836+45G>A		intron	N/A	ENSP00000355106.3
	AGL	ENST00000294724.8	TSL:1	c.3836+45G>A		intron	N/A	ENSP00000294724.4
	AGL	ENST00000370163.7	TSL:1	c.3836+45G>A		intron	N/A	ENSP00000359182.3

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70337 AN: 151300 Hom.: 16702 Cov.: 31

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.378

Gnomad EAS AF: 0.569

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.502

Gnomad MID AF: 0.395

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.470

GnomAD2 exomes AF: 0.482 AC: 115140 AN: 238790 AF XY: 0.474

Gnomad AFR exome AF: 0.371

Gnomad AMR exome AF: 0.571

Gnomad ASJ exome AF: 0.378

Gnomad EAS exome AF: 0.543

Gnomad FIN exome AF: 0.493

Gnomad NFE exome AF: 0.500

Gnomad OTH exome AF: 0.478

GnomAD4 exome AF: 0.502 AC: 718768 AN: 1430636 Hom.: 183175 Cov.: 26 AF XY: 0.497 AC XY: 354033 AN XY: 712122

African (AFR) AF: 0.370 AC: 12017 AN: 32496

American (AMR) AF: 0.565 AC: 24652 AN: 43610

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 10000 AN: 25646

East Asian (EAS) AF: 0.612 AC: 23533 AN: 38424

South Asian (SAS) AF: 0.369 AC: 31154 AN: 84496

European-Finnish (FIN) AF: 0.502 AC: 26093 AN: 51940

Middle Eastern (MID) AF: 0.354 AC: 2007 AN: 5662

European-Non Finnish (NFE) AF: 0.515 AC: 560979 AN: 1089410

Other (OTH) AF: 0.481 AC: 28333 AN: 58952

GnomAD4 genome AF: 0.465 AC: 70402 AN: 151418 Hom.: 16725 Cov.: 31 AF XY: 0.463 AC XY: 34233 AN XY: 73966

African (AFR) AF: 0.372 AC: 15379 AN: 41344

American (AMR) AF: 0.509 AC: 7766 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.378 AC: 1310 AN: 3462

East Asian (EAS) AF: 0.569 AC: 2926 AN: 5140

South Asian (SAS) AF: 0.377 AC: 1808 AN: 4798

European-Finnish (FIN) AF: 0.502 AC: 5248 AN: 10448

Middle Eastern (MID) AF: 0.384 AC: 112 AN: 292

European-Non Finnish (NFE) AF: 0.509 AC: 34472 AN: 67682

Other (OTH) AF: 0.475 AC: 998 AN: 2100

Alfa AF: 0.487 Hom.: 45472

Bravo AF: 0.468

Asia WGS AF: 0.477 AC: 1661 AN: 3476

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.65
DANN	Benign	0.20
PhyloP100		-0.29
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: rs2274570; hg19: chr1-100376448; COSMIC: COSV54050212;