chr2-170816857-G-A
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The ENST00000375272.5(GAD1):c.-259G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00354 in 150,710 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0035 ( 1 hom., cov: 31)
Exomes 𝑓: 0.010 ( 2 hom. )
Consequence
GAD1
ENST00000375272.5 5_prime_UTR
ENST00000375272.5 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.639
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 Benign. Variant got -7 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.32).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00348 (520/149444) while in subpopulation NFE AF= 0.00572 (385/67256). AF 95% confidence interval is 0.00525. There are 1 homozygotes in gnomad4. There are 235 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
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAD1 | XM_011510922.1 | c.-63-1672G>A | intron_variant | ||||
GAD1 | NM_000817.3 | upstream_gene_variant | ENST00000358196.8 | ||||
GAD1 | NM_013445.4 | upstream_gene_variant | |||||
GAD1 | XM_017003758.3 | upstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ENST00000663207.1 | n.335C>T | non_coding_transcript_exon_variant | 1/2 | ||||||
GAD1 | ENST00000358196.8 | upstream_gene_variant | 1 | NM_000817.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00348 AC: 520AN: 149304Hom.: 1 Cov.: 31
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GnomAD4 exome AF: 0.0103 AC: 13AN: 1266Hom.: 2 Cov.: 0 AF XY: 0.0106 AC XY: 7AN XY: 662
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GnomAD4 genome AF: 0.00348 AC: 520AN: 149444Hom.: 1 Cov.: 31 AF XY: 0.00322 AC XY: 235AN XY: 73010
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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 12, 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