rs148143485

chr16-8768841-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020686.6(ABAT):c.684G>A(p.Thr228=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,614,148 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (36 hom.)
• Consequence: ABAT NM_020686.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.11

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 16-8768841-G-A is Benign according to our data. Variant chr16-8768841-G-A is described in ClinVar as [Benign]. Clinvar id is 193917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.11 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000887 (135/152284) while in subpopulation SAS AF= 0.017 (82/4828). AF 95% confidence interval is 0.014. There are 0 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABAT	NM_020686.6	c.684G>A	p.Thr228=	synonymous_variant	11/16	ENST00000268251.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABAT	ENST00000268251.13	c.684G>A	p.Thr228=	synonymous_variant	11/16	1	NM_020686.6	P1

Frequencies

GnomAD3 genomes AF: 0.000894 AC: 136 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00296 AC: 744 AN: 251462 Hom.: 12 AF XY: 0.00388 AC XY: 527 AN XY: 135896

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00299

Gnomad SAS exome AF: 0.0204

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00142 AC: 2074 AN: 1461864 Hom.: 36 Cov.: 32 AF XY: 0.00203 AC XY: 1479 AN XY: 727230

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.000727

Gnomad4 EAS exome AF: 0.00176

Gnomad4 SAS exome AF: 0.0200

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000818

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.000887 AC: 135 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74472

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00289

Gnomad4 SAS AF: 0.0170

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000336 Hom.: 0

Bravo AF: 0.000540

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 23, 2019	- -

Gamma-aminobutyric acid transaminase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	3.1
Dann	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs148143485; hg19: chr16-8862698; COSMIC: COSV51627300;