rs17857148
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong
The NM_000817.3(GAD1):c.872A>G(p.His291Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: not found (cov: 32)
Consequence
GAD1
NM_000817.3 missense
NM_000817.3 missense
Scores
10
3
2
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 8.95
Genes affected
GAD1 (HGNC:4092): (glutamate decarboxylase 1) This gene encodes one of several forms of glutamic acid decarboxylase, identified as a major autoantigen in insulin-dependent diabetes. The enzyme encoded is responsible for catalyzing the production of gamma-aminobutyric acid from L-glutamic acid. A pathogenic role for this enzyme has been identified in the human pancreas since it has been identified as an autoantigen and an autoreactive T cell target in insulin-dependent diabetes. This gene may also play a role in the stiff man syndrome. Deficiency in this enzyme has been shown to lead to pyridoxine dependency with seizures. Alternative splicing of this gene results in two products, the predominant 67-kD form and a less-frequent 25-kD form. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, GAD1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.982
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAD1 | NM_000817.3 | c.872A>G | p.His291Arg | missense_variant | 9/17 | ENST00000358196.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAD1 | ENST00000358196.8 | c.872A>G | p.His291Arg | missense_variant | 9/17 | 1 | NM_000817.3 | P1 | |
GAD1 | ENST00000493875.5 | c.872A>G | p.His291Arg | missense_variant, NMD_transcript_variant | 8/17 | 1 | |||
GAD1 | ENST00000625689.2 | c.872A>G | p.His291Arg | missense_variant | 9/18 | 5 | |||
GAD1 | ENST00000414527.6 | c.*57A>G | 3_prime_UTR_variant, NMD_transcript_variant | 8/16 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;H
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
Sift4G
Pathogenic
D;D
Polyphen
1.0
.;D
Vest4
MutPred
Gain of catalytic residue at H291 (P = 0.0117);Gain of catalytic residue at H291 (P = 0.0117);
MVP
MPC
1.7
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at