rs3749034

Positions:

• chr2-170816965-G-A
• chr2-170816965-G-C
• chr2-170816965-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000817.3(GAD1):​c.-147G>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 0.187 in 195,752 control chromosomes in the GnomAD database, including 4,099 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2949 hom., cov: 31)
  • Exomes 𝑓: 0.22 (1150 hom.)
• Consequence: GAD1 NM_000817.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.250

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 2-170816965-G-A is Benign according to our data. Variant chr2-170816965-G-A is described in ClinVar as [Benign]. Clinvar id is 332221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-170816965-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAD1	NM_000817.3	c.-147G>A		5_prime_UTR_variant	1/17	ENST00000358196.8
GAD1	NM_013445.4	c.-151G>A		5_prime_UTR_variant	1/7
GAD1	XM_017003758.3	c.-147G>A		5_prime_UTR_variant	1/8
GAD1	XM_011510922.1	c.-63-1564G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAD1	ENST00000358196.8	c.-147G>A		5_prime_UTR_variant	1/17	1	NM_000817.3	P1
	ENST00000663207.1	n.227C>T		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27101 AN: 152094 Hom.: 2949 Cov.: 31

Gnomad AFR AF: 0.0443

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.188

GnomAD4 exome AF: 0.220 AC: 9592 AN: 43540 Hom.: 1150 Cov.: 0 AF XY: 0.225 AC XY: 5114 AN XY: 22748

Gnomad4 AFR exome AF: 0.0543

Gnomad4 AMR exome AF: 0.195

Gnomad4 ASJ exome AF: 0.262

Gnomad4 EAS exome AF: 0.279

Gnomad4 SAS exome AF: 0.214

Gnomad4 FIN exome AF: 0.245

Gnomad4 NFE exome AF: 0.214

Gnomad4 OTH exome AF: 0.192

GnomAD4 genome AF: 0.178 AC: 27099 AN: 152212 Hom.: 2949 Cov.: 31 AF XY: 0.182 AC XY: 13515 AN XY: 74416

Gnomad4 AFR AF: 0.0442

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.260

Gnomad4 EAS AF: 0.287

Gnomad4 SAS AF: 0.225

Gnomad4 FIN AF: 0.256

Gnomad4 NFE AF: 0.228

Gnomad4 OTH AF: 0.189

Alfa AF: 0.215 Hom.: 5017

Bravo AF: 0.167

Asia WGS AF: 0.217 AC: 755 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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	-0.43
CADD	Benign	15
DANN	Benign	0.94

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: rs3749034; hg19: chr2-171673475;