ENST00000375272:c.-296C>T

Variant names:

• chr2-170816820-C-T
• rs572158214
• ENST00000375272.5:c.-296C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The ENST00000375272.5(GAD1):​c.-296C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0034 in 154,516 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (5 hom., cov: 31)
  • Exomes 𝑓: 0.00044 (0 hom.)
• Consequence: GAD1 ENST00000375272.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.91
• Publications: 0 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]

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

GAD1-AS1 (HGNC:40250):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00344 (524/152266) while in subpopulation AFR AF = 0.0118 (489/41560). AF 95% confidence interval is 0.0109. There are 5 homozygotes in GnomAd4. There are 250 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000375272.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1-AS1	NR_197761.1		n.643+34G>A		intron	N/A
	GAD1-AS1	NR_197762.1		n.412+34G>A		intron	N/A
	GAD1-AS1	NR_197763.1		n.469+34G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1	ENST00000375272.5	TSL:1	c.-296C>T		5_prime_UTR	Exon 1 of 7	ENSP00000364421.1	Q99259-3
	GAD1	ENST00000625689.2	TSL:5	c.-292C>T		5_prime_UTR	Exon 1 of 18	ENSP00000486612.1	Q99259-4
	GAD1	ENST00000445006.5	TSL:4	c.-292C>T		5_prime_UTR	Exon 2 of 4	ENSP00000394948.1	C9JN45

Frequencies

GnomAD3 genomes AF: 0.00340 AC: 518 AN: 152146 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.000444 AC: 1 AN: 2250 Hom.: 0 Cov.: 0 AF XY: 0.000813 AC XY: 1 AN XY: 1230

African (AFR) AF: 0.0208 AC: 1 AN: 48

American (AMR) AF: 0.00 AC: 0 AN: 40

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 46

East Asian (EAS) AF: 0.00 AC: 0 AN: 246

South Asian (SAS) AF: 0.00 AC: 0 AN: 12

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 8

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1436

Other (OTH) AF: 0.00 AC: 0 AN: 130

GnomAD4 genome AF: 0.00344 AC: 524 AN: 152266 Hom.: 5 Cov.: 31 AF XY: 0.00336 AC XY: 250 AN XY: 74444

African (AFR) AF: 0.0118 AC: 489 AN: 41560

American (AMR) AF: 0.00190 AC: 29 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00291 Hom.: 0

Bravo AF: 0.00389

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	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	-0.25
CADD	Benign	20
DANN	Benign	0.95
PhyloP100		1.9
PromoterAI		-0.12	Neutral
Mutation Taster		=295/5	polymorphism

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: rs572158214; hg19: chr2-171673330;