16-8735747-C-A

Variant summary

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

The NM_020686.6(ABAT):c.8C>A(p.Ser3Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ABAT NM_020686.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.369

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=0.14518753).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABAT	NM_020686.6	c.8C>A	p.Ser3Tyr	missense_variant	2/16	ENST00000268251.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABAT	ENST00000268251.13	c.8C>A	p.Ser3Tyr	missense_variant	2/16	1	NM_020686.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452550 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721562

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000229

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 29, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	0.0058	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.030	T;T;.;T;T;.;.;T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.54	D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	2.0	M;.;.;.;M;.;.;M;.
MutationTaster	Benign	0.94	N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.29	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.089	T;D;T;T;T;T;T;T;D
Sift4G	Benign	0.26	T;T;D;T;T;T;T;T;D
Polyphen		0.097	B;.;.;.;B;.;.;B;.
Vest4		0.40
MutPred		0.27		Loss of disorder (P = 0.0204);.;Loss of disorder (P = 0.0204);Loss of disorder (P = 0.0204);Loss of disorder (P = 0.0204);Loss of disorder (P = 0.0204);.;Loss of disorder (P = 0.0204);Loss of disorder (P = 0.0204);
MVP		0.78
MPC		0.57
ClinPred		0.30	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.037
gMVP		0.55

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: rs762912862; hg19: chr16-8829604;