Genetic Variant ABAT:p.Arg9His (chr16-8735765-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_020686.6(ABAT):c.26G>A(p.Arg9His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,607,346 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R9C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 2 hom. )

Consequence

ABAT
NM_020686.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.739

Publications

1 publications found

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]

ABAT Gene-Disease associations (from GenCC):

GABA aminotransaminase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Orphanet
genetic developmental and epileptic encephalopathy
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ABAT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015526354).

BP6

Variant 16-8735765-G-A is Benign according to our data. Variant chr16-8735765-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 320839.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000138 (21/152268) while in subpopulation SAS AF = 0.00104 (5/4826). AF 95% confidence interval is 0.000408. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020686.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABAT	NM_020686.6	MANE Select	c.26G>A	p.Arg9His	missense	Exon 2 of 16	NP_065737.2
ABAT	NM_001386615.1		c.26G>A	p.Arg9His	missense	Exon 2 of 17	NP_001373544.1
ABAT	NM_001386616.1		c.26G>A	p.Arg9His	missense	Exon 2 of 16	NP_001373545.1	H3BNQ7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABAT	ENST00000268251.13	TSL:1 MANE Select	c.26G>A	p.Arg9His	missense	Exon 2 of 16	ENSP00000268251.8	P80404
ABAT	ENST00000569156.5	TSL:1	c.26G>A	p.Arg9His	missense	Exon 2 of 16	ENSP00000454963.1	H3BNQ7
ABAT	ENST00000566590.5	TSL:1	n.26G>A		non_coding_transcript_exon	Exon 2 of 15	ENSP00000455198.1	H3BP84

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000273

AC:

AN:

238074

AF XY:

0.000372

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000214

Gnomad OTH exome

AF:

0.000516

GnomAD4 exome

AF:

0.000230

AC:

334

AN:

1455078

Hom.:

Cov.:

AF XY:

0.000274

AC XY:

198

AN XY:

723162

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

43934

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25892

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39602

South Asian (SAS)

AF:

0.00145

AC:

123

AN:

84650

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52420

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000166

AC:

184

AN:

1109212

Other (OTH)

AF:

0.000332

AC:

AN:

60152

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000138

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41554

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00104

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000249

Hom.:

Bravo

AF:

0.000113

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000305

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Gamma-aminobutyric acid transaminase deficiency (2)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.038

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.71

M_CAP

Benign

0.017

MetaRNN

Benign

0.016

MetaSVM

Benign

-0.80

MutationAssessor

Benign

-0.55

PhyloP100

0.74

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.4

REVEL

Benign

0.16

Sift

Benign

0.070

Sift4G

Benign

0.11

Polyphen

0.0020

Vest4

0.29

MVP

0.76

MPC

0.38

ClinPred

0.026

GERP RS

0.63

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.034

gMVP

0.27

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over