chr1-99851053-G-A

Variant names:

• chr1-99851053-G-A
• rs1257997077
• NM_000642.3:c.11G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000642.3(AGL):​c.11G>A​(p.Ser4Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000806 in 1,613,812 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S4S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (1 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 4.31
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10734919).

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.11G>A	p.Ser4Asn	missense	Exon 2 of 34	NP_000633.2	P35573-1
	AGL	NM_000028.3		c.11G>A	p.Ser4Asn	missense	Exon 2 of 34	NP_000019.2	P35573-1
	AGL	NM_000643.3		c.11G>A	p.Ser4Asn	missense	Exon 2 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.11G>A	p.Ser4Asn	missense	Exon 2 of 34	ENSP00000355106.3	P35573-1
	AGL	ENST00000294724.8	TSL:1	c.11G>A	p.Ser4Asn	missense	Exon 2 of 34	ENSP00000294724.4	P35573-1
	AGL	ENST00000370163.7	TSL:1	c.11G>A	p.Ser4Asn	missense	Exon 2 of 34	ENSP00000359182.3	P35573-1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251438 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

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: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461600 Hom.: 1 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727126

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111814

Other (OTH) AF: 0.0000166 AC: 1 AN: 60382

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74354

African (AFR) AF: 0.0000241 AC: 1 AN: 41450

American (AMR) AF: 0.000523 AC: 8 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

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

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.000136

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	-	Glycogen storage disease type III (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.037	T
Eigen	Benign	0.0099
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.97	L
PhyloP100		4.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.13
Sift	Benign	0.50	T
Sift4G	Benign	0.50	T
Polyphen		0.0020	B
Vest4		0.20
MutPred		0.22		Loss of helix (P = 0.0558)
MVP		0.75
MPC		0.039
ClinPred		0.50	T
GERP RS		5.3
Varity_R		0.13
gMVP		0.29
Mutation Taster		=79/21	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: rs1257997077; hg19: chr1-100316609;