rs769406

chr2-170859949-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000817.3(GAD1):c.*67A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,444,098 control chromosomes in the GnomAD database, including 978 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.025 (134 hom., cov: 32)
  • Exomes 𝑓: 0.023 (844 hom.)
• Consequence: GAD1 NM_000817.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.03

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 2-170859949-A-G is Benign according to our data. Variant chr2-170859949-A-G is described in ClinVar as [Benign]. Clinvar id is 332244.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAD1	NM_000817.3	c.*67A>G		3_prime_UTR_variant	17/17	ENST00000358196.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAD1	ENST00000358196.8	c.*67A>G		3_prime_UTR_variant	17/17	1	NM_000817.3	P1

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3742 AN: 152234 Hom.: 131 Cov.: 32

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0227

Gnomad FIN AF: 0.00687

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.0248

GnomAD4 exome AF: 0.0229 AC: 29643 AN: 1291746 Hom.: 844 Cov.: 18 AF XY: 0.0223 AC XY: 14455 AN XY: 647092

Gnomad4 AFR exome AF: 0.0137

Gnomad4 AMR exome AF: 0.157

Gnomad4 ASJ exome AF: 0.00150

Gnomad4 EAS exome AF: 0.000261

Gnomad4 SAS exome AF: 0.0241

Gnomad4 FIN exome AF: 0.00667

Gnomad4 NFE exome AF: 0.0201

Gnomad4 OTH exome AF: 0.0200

GnomAD4 genome AF: 0.0247 AC: 3757 AN: 152352 Hom.: 134 Cov.: 32 AF XY: 0.0256 AC XY: 1906 AN XY: 74500

Gnomad4 AFR AF: 0.0158

Gnomad4 AMR AF: 0.105

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0219

Gnomad4 FIN AF: 0.00687

Gnomad4 NFE AF: 0.0186

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0236 Hom.: 103

Bravo AF: 0.0317

Asia WGS AF: 0.0250 AC: 87 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.029
Dann	Benign	0.26

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: rs769406; hg19: chr2-171716459;