rs3749035

Variant names:

• chr2-170816270-A-C
• rs3749035
• ENST00000454603.5:c.-63-2259A>C

Variant summary

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

The ENST00000454603.5(GAD1):​c.-63-2259A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 152,244 control chromosomes in the GnomAD database, including 10,211 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 0.36 (10191 hom., cov: 33)
  • Exomes 𝑓: 0.41 (20 hom.)
• Consequence: GAD1 ENST00000454603.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.651

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]

ENSG00000235934 (HGNC:40250):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD1	XM_011510922.1	c.-63-2259A>C		intron_variant	Intron 1 of 16		XP_011509224.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAD1	ENST00000454603.5	c.-63-2259A>C		intron_variant	Intron 1 of 3	4		ENSP00000402366.1
GAD1	ENST00000445006.5	c.-385+14A>C		intron_variant	Intron 1 of 3	4		ENSP00000394948.1
ENSG00000235934	ENST00000663207.1	n.554T>G		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.356 AC: 54053 AN: 151938 Hom.: 10195 Cov.: 33

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.404

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.322

Gnomad NFE AF: 0.431

Gnomad OTH AF: 0.378

GnomAD4 exome AF: 0.411 AC: 78 AN: 190 Hom.: 20 Cov.: 0 AF XY: 0.475 AC XY: 58 AN XY: 122

Gnomad4 AFR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.393

Gnomad4 NFE exome AF: 0.393

Gnomad4 OTH exome AF: 0.900

GnomAD4 genome AF: 0.355 AC: 54053 AN: 152054 Hom.: 10191 Cov.: 33 AF XY: 0.355 AC XY: 26372 AN XY: 74318

Gnomad4 AFR AF: 0.220

Gnomad4 AMR AF: 0.376

Gnomad4 ASJ AF: 0.404

Gnomad4 EAS AF: 0.213

Gnomad4 SAS AF: 0.360

Gnomad4 FIN AF: 0.407

Gnomad4 NFE AF: 0.431

Gnomad4 OTH AF: 0.377

Alfa AF: 0.404 Hom.: 2689

Bravo AF: 0.346

Asia WGS AF: 0.307 AC: 1070 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	12
DANN	Benign	0.72

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3749035; hg19: chr2-171672780;