NM_000642.3:c.3764A>C

Variant names:

• chr1-99910775-A-C
• rs138134718
• NM_000642.3:c.3764A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000642.3(AGL):​c.3764A>C​(p.Asn1255Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1255S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.80
• Publications: 5 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: ClinGen, Ambry Genetics, Laboratory for Molecular Medicine, Myriad Women’s Health, Orphanet, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	NM_000642.3	MANE Select	c.3764A>C	p.Asn1255Thr	missense	Exon 28 of 34	NP_000633.2
	AGL	NM_000028.3		c.3764A>C	p.Asn1255Thr	missense	Exon 28 of 34	NP_000019.2
	AGL	NM_000643.3		c.3764A>C	p.Asn1255Thr	missense	Exon 28 of 34	NP_000634.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	ENST00000361915.8	TSL:1 MANE Select	c.3764A>C	p.Asn1255Thr	missense	Exon 28 of 34	ENSP00000355106.3
	AGL	ENST00000294724.8	TSL:1	c.3764A>C	p.Asn1255Thr	missense	Exon 28 of 34	ENSP00000294724.4
	AGL	ENST00000370163.7	TSL:1	c.3764A>C	p.Asn1255Thr	missense	Exon 28 of 34	ENSP00000359182.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251026 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 1460746 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726686

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.0000671 AC: 3 AN: 44702

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111188

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		8.8
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.82		Gain of sheet (P = 0.0477)
MVP		0.93
MPC		0.30
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.72
gMVP		0.97
Mutation Taster		=26/74	disease causing

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: rs138134718; hg19: chr1-100376331;