rs1641022

Positions:

• chr16-8774919-C-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_020686.6(ABAT):​c.984C>A​(p.Val328=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 1,613,810 control chromosomes in the GnomAD database, including 138,819 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9839 hom., cov: 32)
  • Exomes 𝑓: 0.42 (128980 hom.)
• Consequence: ABAT NM_020686.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0640

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 16-8774919-C-A is Benign according to our data. Variant chr16-8774919-C-A is described in ClinVar as [Benign]. Clinvar id is 321082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-8774919-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABAT	NM_020686.6	c.984C>A	p.Val328=	synonymous_variant	13/16	ENST00000268251.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABAT	ENST00000268251.13	c.984C>A	p.Val328=	synonymous_variant	13/16	1	NM_020686.6	P1

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50391 AN: 151928 Hom.: 9846 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.341

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.360

Gnomad EAS AF: 0.398

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.513

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.338

GnomAD3 exomes AF: 0.388 AC: 97623 AN: 251384 Hom.: 19903 AF XY: 0.396 AC XY: 53821 AN XY: 135876

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.331

Gnomad ASJ exome AF: 0.361

Gnomad EAS exome AF: 0.393

Gnomad SAS exome AF: 0.393

Gnomad FIN exome AF: 0.496

Gnomad NFE exome AF: 0.426

Gnomad OTH exome AF: 0.379

GnomAD4 exome AF: 0.416 AC: 608489 AN: 1461762 Hom.: 128980 Cov.: 63 AF XY: 0.416 AC XY: 302806 AN XY: 727162

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.327

Gnomad4 ASJ exome AF: 0.366

Gnomad4 EAS exome AF: 0.385

Gnomad4 SAS exome AF: 0.393

Gnomad4 FIN exome AF: 0.485

Gnomad4 NFE exome AF: 0.432

Gnomad4 OTH exome AF: 0.387

GnomAD4 genome AF: 0.331 AC: 50383 AN: 152048 Hom.: 9839 Cov.: 32 AF XY: 0.337 AC XY: 25013 AN XY: 74316

Gnomad4 AFR AF: 0.120

Gnomad4 AMR AF: 0.312

Gnomad4 ASJ AF: 0.360

Gnomad4 EAS AF: 0.398

Gnomad4 SAS AF: 0.384

Gnomad4 FIN AF: 0.513

Gnomad4 NFE AF: 0.426

Gnomad4 OTH AF: 0.334

Alfa AF: 0.396 Hom.: 16901

Bravo AF: 0.309

Asia WGS AF: 0.348 AC: 1209 AN: 3478

EpiCase AF: 0.427

EpiControl AF: 0.427

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2016	- -

Gamma-aminobutyric acid transaminase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	4.9
DANN	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1641022; hg19: chr16-8868776; COSMIC: COSV51622298;