1-99912417-T-C

Variant names:

• chr1-99912417-T-C
• rs28730706
• NM_000642.3:c.3849T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000642.3(AGL):​c.3849T>C​(p.Ala1283Ala) 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:10
• Conservation: PhyloP100: 1.28
• Publications: 4 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: Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 256745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

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.3849T>C	p.Ala1283Ala	synonymous	Exon 29 of 34	NP_000633.2	P35573-1
	AGL	NM_000028.3		c.3849T>C	p.Ala1283Ala	synonymous	Exon 29 of 34	NP_000019.2	P35573-1
	AGL	NM_000643.3		c.3849T>C	p.Ala1283Ala	synonymous	Exon 29 of 34	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.3849T>C	p.Ala1283Ala	synonymous	Exon 29 of 34	ENSP00000355106.3	P35573-1
	AGL	ENST00000294724.8	TSL:1	c.3849T>C	p.Ala1283Ala	synonymous	Exon 29 of 34	ENSP00000294724.4	P35573-1
	AGL	ENST00000370163.7	TSL:1	c.3849T>C	p.Ala1283Ala	synonymous	Exon 29 of 34	ENSP00000359182.3	P35573-1

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

GnomAD2 exomes AF: 0.0137 AC: 3452 AN: 251234 AF XY: 0.0138

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 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

African (AFR) AF: 0.00302 AC: 101 AN: 33478

American (AMR) AF: 0.00738 AC: 330 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0290 AC: 757 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39660

South Asian (SAS) AF: 0.00451 AC: 389 AN: 86252

European-Finnish (FIN) AF: 0.0348 AC: 1859 AN: 53392

Middle Eastern (MID) AF: 0.0444 AC: 256 AN: 5764

European-Non Finnish (NFE) AF: 0.0133 AC: 14742 AN: 1111698

Other (OTH) AF: 0.0148 AC: 892 AN: 60374

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

African (AFR) AF: 0.00260 AC: 108 AN: 41590

American (AMR) AF: 0.0141 AC: 216 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 102 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4830

European-Finnish (FIN) AF: 0.0363 AC: 385 AN: 10600

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0162 AC: 1099 AN: 68032

Other (OTH) AF: 0.0208 AC: 44 AN: 2114

Alfa AF: 0.0145 Hom.: 33

Bravo AF: 0.0104

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0172

EpiControl AF: 0.0167

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Glycogen storage disease type III (4)
-	-	4	not provided (4)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	9.0
DANN	Benign	0.61
PhyloP100		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=90/10	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: rs28730706; hg19: chr1-100377973;