1-99913697-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000642.3(AGL):​c.4120G>T​(p.Asp1374Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1374H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

AGL
NM_000642.3 missense

Scores

14
3
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.58
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AGLNM_000642.3 linkc.4120G>T p.Asp1374Tyr missense_variant Exon 30 of 34 ENST00000361915.8 NP_000633.2 P35573-1A0A0S2A4E4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AGLENST00000361915.8 linkc.4120G>T p.Asp1374Tyr missense_variant Exon 30 of 34 1 NM_000642.3 ENSP00000355106.3 P35573-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Mar 14, 2024
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Benign
0.41
T;T;T;T;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.95
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;.;.;.;D
M_CAP
Pathogenic
0.32
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D
MetaSVM
Uncertain
0.67
D
MutationAssessor
Pathogenic
4.1
H;H;H;H;.
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-7.8
D;D;D;D;D
REVEL
Pathogenic
0.90
Sift
Pathogenic
0.0
D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
1.0
D;D;D;D;D
Vest4
0.99
MutPred
0.90
Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);.;
MVP
0.97
MPC
0.32
ClinPred
1.0
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.97
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-100379253; API