rs3753494

Positions:

• chr1-99892547-C-A
• chr1-99892547-C-G
• chr1-99892547-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000642.3(AGL):​c.3199C>A​(p.Pro1067Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,338 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.28

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGL	NM_000642.3	c.3199C>A	p.Pro1067Thr	missense_variant	24/34	ENST00000361915.8	NP_000633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8	c.3199C>A	p.Pro1067Thr	missense_variant	24/34	1	NM_000642.3	ENSP00000355106	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461338 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726974

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Benign	0.32	T;T;T;T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.044
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;.;.;.;D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.3	M;M;M;M;.
MutationTaster	Benign	3.3e-10	P;P;P;P;P;P;P
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.6	D;D;D;D;D
REVEL	Uncertain	0.40
Sift	Benign	0.14	T;T;T;T;T
Sift4G	Benign	0.17	T;T;T;T;T
Polyphen		0.15	B;B;B;B;B
Vest4		0.75
MutPred		0.37		Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);.;
MVP		0.85
MPC		0.051
ClinPred		0.75	D
GERP RS		5.2
Varity_R		0.19
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs3753494; hg19: chr1-100358103;