rs368127499

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_020686.6(ABAT):​c.1274G>A​(p.Arg425Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000744 in 1,613,922 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R425L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

ABAT
NM_020686.6 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.72
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.122612834).
BS1
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000746 (109/1461658) while in subpopulation EAS AF= 0.000504 (20/39696). AF 95% confidence interval is 0.000333. There are 0 homozygotes in gnomad4_exome. There are 57 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ABATNM_020686.6 linkuse as main transcriptc.1274G>A p.Arg425Gln missense_variant 15/16 ENST00000268251.13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ABATENST00000268251.13 linkuse as main transcriptc.1274G>A p.Arg425Gln missense_variant 15/161 NM_020686.6 P1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152146
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000636
AC:
16
AN:
251376
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135878
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000489
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000746
AC:
109
AN:
1461658
Hom.:
0
Cov.:
32
AF XY:
0.0000784
AC XY:
57
AN XY:
727130
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000504
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000755
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000722
AC:
11
AN:
152264
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74452
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000579
Hom.:
0
Bravo
AF:
0.0000491
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000741
AC:
9

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 07, 2022The c.1274G>A (p.R425Q) alteration is located in exon 15 (coding exon 14) of the ABAT gene. This alteration results from a G to A substitution at nucleotide position 1274, causing the arginine (R) at amino acid position 425 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Gamma-aminobutyric acid transaminase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 15, 2022This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 425 of the ABAT protein (p.Arg425Gln). This variant is present in population databases (rs368127499, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ABAT-related conditions. ClinVar contains an entry for this variant (Variation ID: 572999). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.075
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.40
CADD
Benign
16
DANN
Uncertain
0.99
DEOGEN2
Benign
0.24
T;T;.;T;T
Eigen
Benign
-0.36
Eigen_PC
Benign
-0.18
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.84
.;T;T;.;T
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.12
T;T;T;T;T
MetaSVM
Benign
-0.78
T
MutationAssessor
Benign
0.76
N;N;.;N;.
MutationTaster
Benign
0.74
D;D;D;D;D
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-0.31
N;N;N;N;N
REVEL
Benign
0.11
Sift
Benign
0.55
T;T;T;T;T
Sift4G
Benign
0.42
T;T;T;T;T
Polyphen
0.0020
B;B;.;B;.
Vest4
0.26
MVP
0.74
MPC
0.36
ClinPred
0.057
T
GERP RS
3.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.038
gMVP
0.65

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs368127499; hg19: chr16-8873340; COSMIC: COSV51619881; COSMIC: COSV51619881; API