chr1-99884201-A-G

Variant names:

• chr1-99884201-A-G
• rs149210307
• NM_000642.3:c.2390A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000642.3(AGL):​c.2390A>G​(p.Asn797Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00283 in 1,613,298 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (14 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:6 O:2
• Conservation: PhyloP100: 8.63
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020510167).
• BP6: Variant 1-99884201-A-G is Benign according to our data. Variant chr1-99884201-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 456470.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00205 (312/152328) while in subpopulation NFE AF = 0.00284 (193/67994). AF 95% confidence interval is 0.00251. There are 3 homozygotes in GnomAd4. There are 132 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.2390A>G	p.Asn797Ser	missense	Exon 18 of 34	NP_000633.2	P35573-1
	AGL	NM_000028.3		c.2390A>G	p.Asn797Ser	missense	Exon 18 of 34	NP_000019.2	P35573-1
	AGL	NM_000643.3		c.2390A>G	p.Asn797Ser	missense	Exon 18 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.2390A>G	p.Asn797Ser	missense	Exon 18 of 34	ENSP00000355106.3	P35573-1
	AGL	ENST00000294724.8	TSL:1	c.2390A>G	p.Asn797Ser	missense	Exon 18 of 34	ENSP00000294724.4	P35573-1
	AGL	ENST00000370163.7	TSL:1	c.2390A>G	p.Asn797Ser	missense	Exon 18 of 34	ENSP00000359182.3	P35573-1

Frequencies

GnomAD3 genomes AF: 0.00205 AC: 312 AN: 152210 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.0824

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00284

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00176 AC: 441 AN: 250870 AF XY: 0.00186

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000740

Gnomad NFE exome AF: 0.00279

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00291 AC: 4254 AN: 1460970 Hom.: 14 Cov.: 31 AF XY: 0.00282 AC XY: 2050 AN XY: 726850

African (AFR) AF: 0.000359 AC: 12 AN: 33448

American (AMR) AF: 0.00224 AC: 100 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86230

European-Finnish (FIN) AF: 0.000749 AC: 40 AN: 53406

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5758

European-Non Finnish (NFE) AF: 0.00352 AC: 3908 AN: 1111404

Other (OTH) AF: 0.00253 AC: 153 AN: 60364

GnomAD4 genome AF: 0.00205 AC: 312 AN: 152328 Hom.: 3 Cov.: 32 AF XY: 0.00177 AC XY: 132 AN XY: 74484

African (AFR) AF: 0.000216 AC: 9 AN: 41592

American (AMR) AF: 0.00183 AC: 28 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.000470 AC: 5 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00284 AC: 193 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00136 Hom.: 12

Bravo AF: 0.00261

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00152 AC: 185

EpiCase AF: 0.00262

EpiControl AF: 0.00373

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	3	Glycogen storage disease type III (8)
-	2	2	not provided (5)
-	-	1	AGL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		8.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.20
Sift	Benign	0.064	T
Sift4G	Benign	0.10	T
Polyphen		0.80	P
Vest4		0.77
MVP		0.58
MPC		0.13
ClinPred		0.045	T
GERP RS		5.8
Varity_R		0.43
gMVP		0.61
Mutation Taster		=100/0	polymorphism

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: rs149210307; hg19: chr1-100349757;