rs78348923

Variant names:

• chr1-99916680-C-G
• rs78348923
• NM_000642.3:c.4430C>G

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.4430C>G​(p.Thr1477Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000865 in 1,613,216 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1477T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0049 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (2 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.85
• Publications: 1 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

ENSG00000288826 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065066814).
• BP6: Variant 1-99916680-C-G is Benign according to our data. Variant chr1-99916680-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377192.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 = 0.00494 (751/152136) while in subpopulation AFR AF = 0.0172 (713/41512). AF 95% confidence interval is 0.0161. There are 4 homozygotes in GnomAd4. There are 360 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.4430C>G	p.Thr1477Ser	missense	Exon 33 of 34	NP_000633.2	P35573-1
	AGL	NM_000028.3		c.4430C>G	p.Thr1477Ser	missense	Exon 33 of 34	NP_000019.2	P35573-1
	AGL	NM_000643.3		c.4430C>G	p.Thr1477Ser	missense	Exon 33 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.4430C>G	p.Thr1477Ser	missense	Exon 33 of 34	ENSP00000355106.3	P35573-1
	AGL	ENST00000294724.8	TSL:1	c.4430C>G	p.Thr1477Ser	missense	Exon 33 of 34	ENSP00000294724.4	P35573-1
	AGL	ENST00000370163.7	TSL:1	c.4430C>G	p.Thr1477Ser	missense	Exon 33 of 34	ENSP00000359182.3	P35573-1

Frequencies

GnomAD3 genomes AF: 0.00493 AC: 749 AN: 152018 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

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: 0.00431

GnomAD2 exomes AF: 0.00120 AC: 301 AN: 250836 AF XY: 0.000885

Gnomad AFR exome AF: 0.0166

Gnomad AMR exome AF: 0.000843

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000441 AC: 645 AN: 1461080 Hom.: 2 Cov.: 31 AF XY: 0.000369 AC XY: 268 AN XY: 726840

African (AFR) AF: 0.0161 AC: 538 AN: 33448

American (AMR) AF: 0.00103 AC: 46 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111542

Other (OTH) AF: 0.000961 AC: 58 AN: 60368

GnomAD4 genome AF: 0.00494 AC: 751 AN: 152136 Hom.: 4 Cov.: 32 AF XY: 0.00484 AC XY: 360 AN XY: 74370

African (AFR) AF: 0.0172 AC: 713 AN: 41512

American (AMR) AF: 0.00177 AC: 27 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67988

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.000536 Hom.: 0

Bravo AF: 0.00526

ESP6500AA AF: 0.0197 AC: 87

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00154 AC: 187

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.11
Sift	Benign	0.20	T
Sift4G	Benign	0.23	T
Polyphen		0.0030	B
Vest4		0.36
MutPred		0.64		Gain of ubiquitination at K1476 (P = 0.0619)
MVP		0.74
MPC		0.041
ClinPred		0.029	T
GERP RS		5.0
Varity_R		0.11
gMVP		0.69
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: rs78348923; hg19: chr1-100382236;