ENST00000375272:c.-248G>A

Variant names:

• chr2-170816868-G-A
• rs576236119
• ENST00000375272.5:c.-248G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000375272.5(GAD1):​c.-248G>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 0.00335 in 158,256 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: GAD1 ENST00000375272.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.973
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 2-170816868-G-A is Benign according to our data. Variant chr2-170816868-G-A is described in ClinVar as Benign. ClinVar VariationId is 332215.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00348 (528/151720) while in subpopulation AFR AF = 0.0119 (492/41390). AF 95% confidence interval is 0.011. There are 5 homozygotes in GnomAd4. There are 251 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• 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.629C>T		non_coding_transcript_exon	Exon 3 of 4
	GAD1-AS1	NR_197762.1		n.398C>T		non_coding_transcript_exon	Exon 2 of 3
	GAD1-AS1	NR_197763.1		n.455C>T		non_coding_transcript_exon	Exon 2 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1	ENST00000375272.5	TSL:1	c.-248G>A		5_prime_UTR	Exon 1 of 7	ENSP00000364421.1	Q99259-3
	GAD1	ENST00000625689.2	TSL:5	c.-244G>A		5_prime_UTR	Exon 1 of 18	ENSP00000486612.1	Q99259-4
	GAD1	ENST00000445006.5	TSL:4	c.-244G>A		5_prime_UTR	Exon 2 of 4	ENSP00000394948.1	C9JN45

Frequencies

GnomAD3 genomes AF: 0.00344 AC: 522 AN: 151602 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00240

GnomAD4 exome AF: 0.000306 AC: 2 AN: 6536 Hom.: 0 Cov.: 0 AF XY: 0.000569 AC XY: 2 AN XY: 3514

African (AFR) AF: 0.0130 AC: 2 AN: 154

American (AMR) AF: 0.00 AC: 0 AN: 128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 162

East Asian (EAS) AF: 0.00 AC: 0 AN: 696

South Asian (SAS) AF: 0.00 AC: 0 AN: 70

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 642

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 32

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4356

Other (OTH) AF: 0.00 AC: 0 AN: 296

GnomAD4 genome AF: 0.00348 AC: 528 AN: 151720 Hom.: 5 Cov.: 32 AF XY: 0.00338 AC XY: 251 AN XY: 74200

African (AFR) AF: 0.0119 AC: 492 AN: 41390

American (AMR) AF: 0.00190 AC: 29 AN: 15258

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5076

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67848

Other (OTH) AF: 0.00238 AC: 5 AN: 2102

Alfa AF: 0.00291 Hom.: 0

Bravo AF: 0.00388

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

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	-0.61
CADD	Benign	15
DANN	Benign	0.93
PhyloP100		0.97
PromoterAI		0.068	Neutral
Mutation Taster		=298/2	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: rs576236119; hg19: chr2-171673378;