chr2-170818563-A-G
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_000817.3(GAD1):c.-29A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000429 in 1,607,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000045 ( 0 hom. )
Consequence
GAD1
NM_000817.3 5_prime_UTR
NM_000817.3 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.57
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_benign. Variant got -3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.66).
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000197 (3/152174) while in subpopulation SAS AF= 0.000623 (3/4816). AF 95% confidence interval is 0.000169. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| GAD1 | NM_000817.3 | c.-29A>G | 5_prime_UTR_variant | 2/17 | ENST00000358196.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| GAD1 | ENST00000358196.8 | c.-29A>G | 5_prime_UTR_variant | 2/17 | 1 | NM_000817.3 | P1 |
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152056Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000108 AC: 27AN: 251106Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135808
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GnomAD4 exome AF: 0.0000454 AC: 66AN: 1454884Hom.: 0 Cov.: 29 AF XY: 0.0000704 AC XY: 51AN XY: 724318
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GnomAD4 genome 0.0000197 AC: 3AN: 152174Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3AN XY: 74396
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at