rs1555493999

Positions:

• chr16-8779572-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020686.6(ABAT):​c.1363T>G​(p.Leu455Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABAT NM_020686.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.227

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13177612).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABAT	NM_020686.6	c.1363T>G	p.Leu455Val	missense_variant	15/16	ENST00000268251.13	NP_065737.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABAT	ENST00000268251.13	c.1363T>G	p.Leu455Val	missense_variant	15/16	1	NM_020686.6	ENSP00000268251.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gamma-aminobutyric acid transaminase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 14, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 460323). This variant has not been reported in the literature in individuals affected with ABAT-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 455 of the ABAT protein (p.Leu455Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	9.1
DANN	Benign	0.95
DEOGEN2	Benign	0.22	T;T;.;T;T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.84	.;T;T;.;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L;.;L;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.090	N;N;N;N;N
REVEL	Benign	0.028
Sift	Benign	0.29	T;T;T;T;T
Sift4G	Benign	0.29	T;T;T;T;T
Polyphen		0.0	B;B;.;B;.
Vest4		0.24
MutPred		0.29		Gain of methylation at K452 (P = 0.0797);Gain of methylation at K452 (P = 0.0797);.;Gain of methylation at K452 (P = 0.0797);Gain of methylation at K452 (P = 0.0797);
MVP		0.57
MPC		0.31
ClinPred		0.22	T
GERP RS		0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.084
gMVP		0.61

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: rs1555493999; hg19: chr16-8873429; COSMIC: COSV51620131; COSMIC: COSV51620131;