rs545676026

Variant names:

• chr2-170816857-G-A
• rs545676026
• ENST00000375272.5:c.-259G>A

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.-259G>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 0.00354 in 150,710 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 31)
  • Exomes 𝑓: 0.010 (2 hom.)
• Consequence: GAD1 ENST00000375272.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.639
• 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=-0.32).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00348 (520/149444) while in subpopulation NFE AF = 0.00572 (385/67256). AF 95% confidence interval is 0.00525. There are 1 homozygotes in GnomAd4. There are 235 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 GnomAdExome4 at 2 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.640C>T		non_coding_transcript_exon	Exon 3 of 4
	GAD1-AS1	NR_197762.1		n.409C>T		non_coding_transcript_exon	Exon 2 of 3
	GAD1-AS1	NR_197763.1		n.466C>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.-259G>A		5_prime_UTR	Exon 1 of 7	ENSP00000364421.1	Q99259-3
	GAD1	ENST00000625689.2	TSL:5	c.-255G>A		5_prime_UTR	Exon 1 of 18	ENSP00000486612.1	Q99259-4
	GAD1	ENST00000445006.5	TSL:4	c.-255G>A		5_prime_UTR	Exon 2 of 4	ENSP00000394948.1	C9JN45

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 520 AN: 149304 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00108

Gnomad AMI AF: 0.0434

Gnomad AMR AF: 0.00147

Gnomad ASJ AF: 0.00463

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000675

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00572

Gnomad OTH AF: 0.00340

GnomAD4 exome AF: 0.0103 AC: 13 AN: 1266 Hom.: 2 Cov.: 0 AF XY: 0.0106 AC XY: 7 AN XY: 662

African (AFR) AF: 0.00 AC: 0 AN: 20

American (AMR) AF: 0.00 AC: 0 AN: 22

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 40

East Asian (EAS) AF: 0.00 AC: 0 AN: 152

South Asian (SAS) AF: 0.00 AC: 0 AN: 14

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 76

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.0139 AC: 12 AN: 866

Other (OTH) AF: 0.0135 AC: 1 AN: 74

GnomAD4 genome AF: 0.00348 AC: 520 AN: 149444 Hom.: 1 Cov.: 31 AF XY: 0.00322 AC XY: 235 AN XY: 73010

African (AFR) AF: 0.00108 AC: 44 AN: 40760

American (AMR) AF: 0.00147 AC: 22 AN: 14984

Ashkenazi Jewish (ASJ) AF: 0.00463 AC: 16 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 4760

South Asian (SAS) AF: 0.00 AC: 0 AN: 4586

European-Finnish (FIN) AF: 0.000675 AC: 7 AN: 10374

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

European-Non Finnish (NFE) AF: 0.00572 AC: 385 AN: 67256

Other (OTH) AF: 0.00337 AC: 7 AN: 2078

Alfa AF: 0.00444 Hom.: 0

Bravo AF: 0.00361

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.32
CADD	Benign	9.0
DANN	Benign	0.95
PhyloP100		-0.64
PromoterAI		-0.016	Neutral
Mutation Taster		=292/8	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: rs545676026; hg19: chr2-171673367;