Genetic Variant GAD1:c.-158G>A (chr2-170816954-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBA1

The NM_000817.3(GAD1):c.-158G>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 0.0197 in 195,242 control chromosomes in the GnomAD database, including 150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.021 ( 136 hom., cov: 31)

Exomes 𝑓: 0.014 ( 14 hom. )

Consequence

GAD1
NM_000817.3 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.150

Publications

0 publications found

Variant links:

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]

GAD1 links:

ERICH2-DT (HGNC:55686): (ERICH2 divergent transcript)

ERICH2-DT links:

GAD1-AS1 (HGNC:40250):

GAD1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 2-170816954-G-A is Benign according to our data. Variant chr2-170816954-G-A is described in ClinVar as Benign. ClinVar VariationId is 332220.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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000817.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GAD1	NM_000817.3	MANE Select	c.-158G>A	5_prime_UTR	Exon 1 of 17	NP_000808.2	Q99259-1
GAD1	NM_013445.4		c.-162G>A	5_prime_UTR	Exon 1 of 7	NP_038473.2
GAD1-AS1	NR_197761.1		n.543C>T	non_coding_transcript_exon	Exon 3 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GAD1	ENST00000358196.8	TSL:1 MANE Select	c.-158G>A	5_prime_UTR	Exon 1 of 17	ENSP00000350928.3	Q99259-1
GAD1	ENST00000375272.5	TSL:1	c.-162G>A	5_prime_UTR	Exon 1 of 7	ENSP00000364421.1	Q99259-3
GAD1	ENST00000625689.2	TSL:5	c.-158G>A	5_prime_UTR	Exon 1 of 18	ENSP00000486612.1	Q99259-4

Frequencies

GnomAD3 genomes

AF:

0.0212

AC:

3230

AN:

152188

Hom.:

133

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00560

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.104

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0153

Gnomad FIN

AF:

0.00687

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0179

Gnomad OTH

AF:

0.0220

GnomAD4 exome

AF:

0.0141

AC:

607

AN:

42936

Hom.:

Cov.:

AF XY:

0.0147

AC XY:

331

AN XY:

22456

show subpopulations

African (AFR)

AF:

0.00288

AC:

AN:

1040

American (AMR)

AF:

0.0936

AC:

AN:

972

Ashkenazi Jewish (ASJ)

AF:

0.00152

AC:

AN:

1312

East Asian (EAS)

AF:

0.00

AC:

AN:

4452

South Asian (SAS)

AF:

0.0130

AC:

AN:

386

European-Finnish (FIN)

AF:

0.00665

AC:

AN:

4960

Middle Eastern (MID)

AF:

0.0248

AC:

AN:

202

European-Non Finnish (NFE)

AF:

0.0156

AC:

424

AN:

27122

Other (OTH)

AF:

0.0177

AC:

AN:

2490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

109

136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0213

AC:

3240

AN:

152306

Hom.:

136

Cov.:

AF XY:

0.0224

AC XY:

1671

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00558

AC:

232

AN:

41574

American (AMR)

AF:

0.104

AC:

1596

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.0145

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00687

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0179

AC:

1218

AN:

68028

Other (OTH)

AF:

0.0218

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

152

304

457

609

761

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0193

Hom.:

Bravo

AF:

0.0279

Asia WGS

AF:

0.0150

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

0.15

PromoterAI

0.15

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over