rs3749033

chr2-170842889-T-Achr2-170842889-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_000817.3(GAD1):c.639-1156T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 600,982 control chromosomes in the GnomAD database, including 20,716 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.21 (3987 hom., cov: 32)
  • Exomes 𝑓: 0.26 (16729 hom.)
• Consequence: GAD1 NM_000817.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.24

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=-0.43).
• BP6: Variant 2-170842889-T-A is Benign according to our data. Variant chr2-170842889-T-A is described in ClinVar as [Benign]. Clinvar id is 1269663.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAD1	NM_000817.3	c.639-1156T>A		intron_variant		ENST00000358196.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAD1	ENST00000358196.8	c.639-1156T>A		intron_variant		1	NM_000817.3	P1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32215 AN: 152032 Hom.: 3986 Cov.: 32

Gnomad AFR AF: 0.0881

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.293

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.206

GnomAD4 exome AF: 0.264 AC: 118715 AN: 448832 Hom.: 16729 AF XY: 0.270 AC XY: 63237 AN XY: 234056

Gnomad4 AFR exome AF: 0.0867

Gnomad4 AMR exome AF: 0.159

Gnomad4 ASJ exome AF: 0.220

Gnomad4 EAS exome AF: 0.287

Gnomad4 SAS exome AF: 0.364

Gnomad4 FIN exome AF: 0.319

Gnomad4 NFE exome AF: 0.260

Gnomad4 OTH exome AF: 0.246

GnomAD4 genome AF: 0.212 AC: 32226 AN: 152150 Hom.: 3987 Cov.: 32 AF XY: 0.216 AC XY: 16059 AN XY: 74384

Gnomad4 AFR AF: 0.0879

Gnomad4 AMR AF: 0.168

Gnomad4 ASJ AF: 0.225

Gnomad4 EAS AF: 0.293

Gnomad4 SAS AF: 0.368

Gnomad4 FIN AF: 0.316

Gnomad4 NFE AF: 0.264

Gnomad4 OTH AF: 0.209

Alfa AF: 0.230 Hom.: 533

Bravo AF: 0.193

Asia WGS AF: 0.311 AC: 1081 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	16
Dann	Benign	0.82

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: rs3749033; hg19: chr2-171699399;