1-99902713-G-A

Variant names:

• chr1-99902713-G-A
• rs11807956
• NM_000642.3:c.3619G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000642.3(AGL):​c.3619G>A​(p.Ala1207Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00157 in 1,613,444 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0085 (23 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (20 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.02
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006166458).
• BP6: Variant 1-99902713-G-A is Benign according to our data. Variant chr1-99902713-G-A is described in ClinVar as Benign. ClinVar VariationId is 256741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00848 (1291/152284) while in subpopulation AFR AF = 0.0299 (1242/41560). AF 95% confidence interval is 0.0285. There are 23 homozygotes in GnomAd4. There are 597 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 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.3619G>A	p.Ala1207Thr	missense	Exon 27 of 34	NP_000633.2	P35573-1
	AGL	NM_000028.3		c.3619G>A	p.Ala1207Thr	missense	Exon 27 of 34	NP_000019.2	P35573-1
	AGL	NM_000643.3		c.3619G>A	p.Ala1207Thr	missense	Exon 27 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.3619G>A	p.Ala1207Thr	missense	Exon 27 of 34	ENSP00000355106.3	P35573-1
	AGL	ENST00000294724.8	TSL:1	c.3619G>A	p.Ala1207Thr	missense	Exon 27 of 34	ENSP00000294724.4	P35573-1
	AGL	ENST00000370163.7	TSL:1	c.3619G>A	p.Ala1207Thr	missense	Exon 27 of 34	ENSP00000359182.3	P35573-1

Frequencies

GnomAD3 genomes AF: 0.00846 AC: 1287 AN: 152166 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00221 AC: 555 AN: 250652 AF XY: 0.00149

Gnomad AFR exome AF: 0.0306

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000883

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000847 AC: 1238 AN: 1461160 Hom.: 20 Cov.: 30 AF XY: 0.000721 AC XY: 524 AN XY: 726906

African (AFR) AF: 0.0297 AC: 995 AN: 33464

American (AMR) AF: 0.00136 AC: 61 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5764

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111486

Other (OTH) AF: 0.00220 AC: 133 AN: 60348

GnomAD4 genome AF: 0.00848 AC: 1291 AN: 152284 Hom.: 23 Cov.: 32 AF XY: 0.00802 AC XY: 597 AN XY: 74472

African (AFR) AF: 0.0299 AC: 1242 AN: 41560

American (AMR) AF: 0.00235 AC: 36 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00352 Hom.: 3

Bravo AF: 0.00976

ESP6500AA AF: 0.0306 AC: 135

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00286 AC: 347

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Glycogen storage disease type III (3)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		4.0
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.21
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.045	D
Polyphen		0.089	B
Vest4		0.33
MVP		0.76
MPC		0.053
ClinPred		0.093	T
GERP RS		2.0
Varity_R		0.076
gMVP		0.73
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs11807956; hg19: chr1-100368269;