rs747339245

Variant names:

• chr1-99892481-G-C
• rs747339245
• NM_000642.3:c.3133G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-99892481-G-C
• chr1-99892481-G-A
• chr1-99892481-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000642.3(AGL):​c.3133G>C​(p.Val1045Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.93
• 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: Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, Myriad Women’s Health

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23303932).

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.3133G>C	p.Val1045Leu	missense	Exon 24 of 34	NP_000633.2	P35573-1
	AGL	NM_000028.3		c.3133G>C	p.Val1045Leu	missense	Exon 24 of 34	NP_000019.2	P35573-1
	AGL	NM_000643.3		c.3133G>C	p.Val1045Leu	missense	Exon 24 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.3133G>C	p.Val1045Leu	missense	Exon 24 of 34	ENSP00000355106.3	P35573-1
	AGL	ENST00000294724.8	TSL:1	c.3133G>C	p.Val1045Leu	missense	Exon 24 of 34	ENSP00000294724.4	P35573-1
	AGL	ENST00000370163.7	TSL:1	c.3133G>C	p.Val1045Leu	missense	Exon 24 of 34	ENSP00000359182.3	P35573-1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251242 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

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: 0.00000274 AC: 4 AN: 1461374 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726990

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.0000895 AC: 4 AN: 44706

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111710

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74274

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.000131 AC: 2 AN: 15250

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

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: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

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	0.14
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.26
Sift	Benign	0.54	T
Sift4G	Benign	0.50	T
Polyphen		0.0010	B
Vest4		0.19
MutPred		0.62		Loss of catalytic residue at V1045 (P = 0.0188)
MVP		0.68
MPC		0.044
ClinPred		0.35	T
GERP RS		5.2
Varity_R		0.14
gMVP		0.67
Mutation Taster		=84/16	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: rs747339245; hg19: chr1-100358037;