NM_020686.6:c.1269+6A>G

Variant names:

• chr16-8776496-A-G
• rs372790444
• NM_020686.6:c.1269+6A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020686.6(ABAT):​c.1269+6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000941 in 1,604,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000093 (0 hom.)
• Consequence: ABAT NM_020686.6 splice_region, intron
• Scores: Splicing: ADA: 0.000007345
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: -1.24
• Publications: 0 publications found

Genes affected

ABAT (HGNC:23): (4-aminobutyrate aminotransferase) 4-aminobutyrate aminotransferase (ABAT) is responsible for catabolism of gamma-aminobutyric acid (GABA), an important, mostly inhibitory neurotransmitter in the central nervous system, into succinic semialdehyde. The active enzyme is a homodimer of 50-kD subunits complexed to pyridoxal-5-phosphate. The protein sequence is over 95% similar to the pig protein. GABA is estimated to be present in nearly one-third of human synapses. ABAT in liver and brain is controlled by 2 codominant alleles with a frequency in a Caucasian population of 0.56 and 0.44. The ABAT deficiency phenotype includes psychomotor retardation, hypotonia, hyperreflexia, lethargy, refractory seizures, and EEG abnormalities. Multiple alternatively spliced transcript variants encoding the same protein isoform have been found for this gene. [provided by RefSeq, Jul 2008]

ABAT Gene-Disease associations (from GenCC):

• GABA aminotransaminase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Orphanet, G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020686.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABAT	NM_020686.6	MANE Select	c.1269+6A>G		splice_region intron	N/A	NP_065737.2
	ABAT	NM_001386615.1		c.1365+6A>G		splice_region intron	N/A	NP_001373544.1
	ABAT	NM_001386616.1		c.1269+6A>G		splice_region intron	N/A	NP_001373545.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABAT	ENST00000268251.13	TSL:1 MANE Select	c.1269+6A>G		splice_region intron	N/A	ENSP00000268251.8
	ABAT	ENST00000569156.5	TSL:1	c.1269+6A>G		splice_region intron	N/A	ENSP00000454963.1
	ABAT	ENST00000566590.5	TSL:1	n.*1009+6A>G		splice_region intron	N/A	ENSP00000455198.1

Frequencies

GnomAD3 genomes AF: 0.000106 AC: 16 AN: 151604 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000236

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000476 AC: 11 AN: 230968 AF XY: 0.0000557

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000602

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000684

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000929 AC: 135 AN: 1452682 Hom.: 0 Cov.: 32 AF XY: 0.0000886 AC XY: 64 AN XY: 721982

African (AFR) AF: 0.00 AC: 0 AN: 33196

American (AMR) AF: 0.0000458 AC: 2 AN: 43644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25914

East Asian (EAS) AF: 0.00 AC: 0 AN: 39118

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 84950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5144

European-Non Finnish (NFE) AF: 0.000108 AC: 120 AN: 1108630

Other (OTH) AF: 0.000183 AC: 11 AN: 59970

GnomAD4 genome AF: 0.000106 AC: 16 AN: 151604 Hom.: 0 Cov.: 32 AF XY: 0.0000540 AC XY: 4 AN XY: 74032

African (AFR) AF: 0.00 AC: 0 AN: 41260

American (AMR) AF: 0.00 AC: 0 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000236 AC: 16 AN: 67840

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.0000715 Hom.: 0

Bravo AF: 0.000102

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	ABAT-related disorder (1)
-	1	-	Gamma-aminobutyric acid transaminase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.9
DANN	Benign	0.29
PhyloP100		-1.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000073
dbscSNV1_RF	Benign	0.0060
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: rs372790444; hg19: chr16-8870353;