NM_000817.3:c.1184+387A>T

Variant names:

• chr2-170849737-A-T
• rs4668331
• NM_000817.3:c.1184+387A>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000817.3(GAD1):​c.1184+387A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 152,224 control chromosomes in the GnomAD database, including 4,032 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (4032 hom., cov: 32)
• Consequence: GAD1 NM_000817.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0630

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD1	NM_000817.3	c.1184+387A>T		intron_variant	Intron 12 of 16	ENST00000358196.8	NP_000808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAD1	ENST00000358196.8	c.1184+387A>T		intron_variant	Intron 12 of 16	1	NM_000817.3	ENSP00000350928.3

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32787 AN: 152108 Hom.: 4030 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.205

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.212

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.216 AC: 32809 AN: 152224 Hom.: 4032 Cov.: 32 AF XY: 0.220 AC XY: 16358 AN XY: 74424

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.170

Gnomad4 ASJ AF: 0.225

Gnomad4 EAS AF: 0.297

Gnomad4 SAS AF: 0.369

Gnomad4 FIN AF: 0.315

Gnomad4 NFE AF: 0.263

Gnomad4 OTH AF: 0.215

Alfa AF: 0.232 Hom.: 533

Bravo AF: 0.197

Asia WGS AF: 0.317 AC: 1100 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.7
DANN	Benign	0.83

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: rs4668331; hg19: chr2-171706247;