rs3749033

Variant names:

• chr2-170842889-T-A
• rs3749033
• NM_000817.3:c.639-1156T>A

Your query was ambiguous. Multiple possible variants found:

• chr2-170842889-T-A
• chr2-170842889-T-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.24
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• early infantile epileptic encephalopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy 89

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• spastic quadriplegic cerebral palsy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• cerebral palsy, spastic quadriplegic, 1

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -18 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 VariationId is 1269663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
GAD1	NM_000817.3	c.639-1156T>A		intron_variant	Intron 6 of 16	ENST00000358196.8	NP_000808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAD1	ENST00000358196.8	c.639-1156T>A		intron_variant	Intron 6 of 16	1	NM_000817.3	ENSP00000350928.3

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

African (AFR) AF: 0.0867 AC: 1050 AN: 12106

American (AMR) AF: 0.159 AC: 2441 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 2575 AN: 11724

East Asian (EAS) AF: 0.287 AC: 6984 AN: 24352

South Asian (SAS) AF: 0.364 AC: 15619 AN: 42872

European-Finnish (FIN) AF: 0.319 AC: 6989 AN: 21916

Middle Eastern (MID) AF: 0.226 AC: 404 AN: 1790

European-Non Finnish (NFE) AF: 0.260 AC: 76741 AN: 294778

Other (OTH) AF: 0.246 AC: 5912 AN: 23984

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

African (AFR) AF: 0.0879 AC: 3651 AN: 41532

American (AMR) AF: 0.168 AC: 2566 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 780 AN: 3470

East Asian (EAS) AF: 0.293 AC: 1510 AN: 5160

South Asian (SAS) AF: 0.368 AC: 1773 AN: 4824

European-Finnish (FIN) AF: 0.316 AC: 3344 AN: 10570

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17921 AN: 67994

Other (OTH) AF: 0.209 AC: 442 AN: 2112

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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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
PhyloP100		2.2
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3749033; hg19: chr2-171699399;