rs634880

Variant names:

• chr1-99874669-G-A
• rs634880
• NM_000642.3:c.959-18G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-99874669-G-A
• chr1-99874669-G-C

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.959-18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.712 in 1,597,686 control chromosomes in the GnomAD database, including 407,006 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (41324 hom., cov: 32)
  • Exomes 𝑓: 0.71 (365682 hom.)
• Consequence: AGL NM_000642.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.906
• Publications: 10 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: Orphanet, Myriad Women’s Health, Genomics England PanelApp, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 1-99874669-G-A is Benign according to our data. Variant chr1-99874669-G-A is described in ClinVar as Benign. ClinVar VariationId is 256751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.834 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	NM_000642.3	MANE Select	c.959-18G>A		intron	N/A	NP_000633.2	P35573-1
	AGL	NM_000028.3		c.959-18G>A		intron	N/A	NP_000019.2	P35573-1
	AGL	NM_000643.3		c.959-18G>A		intron	N/A	NP_000634.2	A0A0S2A4E4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	ENST00000361915.8	TSL:1 MANE Select	c.959-18G>A		intron	N/A	ENSP00000355106.3	P35573-1
	AGL	ENST00000294724.8	TSL:1	c.959-18G>A		intron	N/A	ENSP00000294724.4	P35573-1
	AGL	ENST00000370163.7	TSL:1	c.959-18G>A		intron	N/A	ENSP00000359182.3	P35573-1

Frequencies

GnomAD3 genomes AF: 0.734 AC: 111364 AN: 151696 Hom.: 41276 Cov.: 32

Gnomad AFR AF: 0.841

Gnomad AMI AF: 0.729

Gnomad AMR AF: 0.687

Gnomad ASJ AF: 0.652

Gnomad EAS AF: 0.721

Gnomad SAS AF: 0.738

Gnomad FIN AF: 0.678

Gnomad MID AF: 0.656

Gnomad NFE AF: 0.694

Gnomad OTH AF: 0.725

GnomAD2 exomes AF: 0.717 AC: 176020 AN: 245452 AF XY: 0.717

Gnomad AFR exome AF: 0.845

Gnomad AMR exome AF: 0.682

Gnomad ASJ exome AF: 0.703

Gnomad EAS exome AF: 0.711

Gnomad FIN exome AF: 0.703

Gnomad NFE exome AF: 0.710

Gnomad OTH exome AF: 0.725

GnomAD4 exome AF: 0.710 AC: 1026190 AN: 1445872 Hom.: 365682 Cov.: 32 AF XY: 0.709 AC XY: 510548 AN XY: 719644

African (AFR) AF: 0.848 AC: 28125 AN: 33170

American (AMR) AF: 0.680 AC: 30119 AN: 44308

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 17743 AN: 25804

East Asian (EAS) AF: 0.704 AC: 27867 AN: 39574

South Asian (SAS) AF: 0.731 AC: 62633 AN: 85692

European-Finnish (FIN) AF: 0.688 AC: 36335 AN: 52790

Middle Eastern (MID) AF: 0.714 AC: 4062 AN: 5690

European-Non Finnish (NFE) AF: 0.707 AC: 776999 AN: 1099098

Other (OTH) AF: 0.708 AC: 42307 AN: 59746

GnomAD4 genome AF: 0.734 AC: 111477 AN: 151814 Hom.: 41324 Cov.: 32 AF XY: 0.734 AC XY: 54466 AN XY: 74198

African (AFR) AF: 0.841 AC: 34929 AN: 41510

American (AMR) AF: 0.686 AC: 10464 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.652 AC: 2247 AN: 3446

East Asian (EAS) AF: 0.720 AC: 3736 AN: 5188

South Asian (SAS) AF: 0.740 AC: 3564 AN: 4818

European-Finnish (FIN) AF: 0.678 AC: 7120 AN: 10502

Middle Eastern (MID) AF: 0.647 AC: 189 AN: 292

European-Non Finnish (NFE) AF: 0.694 AC: 47039 AN: 67812

Other (OTH) AF: 0.730 AC: 1524 AN: 2088

Alfa AF: 0.712 Hom.: 47511

Bravo AF: 0.750

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Glycogen storage disease type III (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	6.1
DANN	Benign	0.36
PhyloP100		-0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs634880; hg19: chr1-100340225; COSMIC: COSV54049593;