Genetic Variant ABAT:p.Arg19Cys (chr16-8735794-C-T) – 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.55C>T(p.Arg19Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000678 in 1,605,756 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts 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. R19S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0032 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 5 hom. )

Consequence

ABAT
NM_020686.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.331

Publications

3 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 Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), 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=0.008483738).

BP6

Variant 16-8735794-C-T is Benign according to our data. Variant chr16-8735794-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235649.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00318 (484/152232) while in subpopulation AFR AF = 0.0108 (449/41536). AF 95% confidence interval is 0.00998. There are 3 homozygotes in GnomAd4. There are 225 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 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.55C>T	p.Arg19Cys	missense	Exon 2 of 16	NP_065737.2
ABAT	NM_001386615.1		c.55C>T	p.Arg19Cys	missense	Exon 2 of 17	NP_001373544.1
ABAT	NM_001386616.1		c.55C>T	p.Arg19Cys	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.55C>T	p.Arg19Cys	missense	Exon 2 of 16	ENSP00000268251.8	P80404
ABAT	ENST00000569156.5	TSL:1	c.55C>T	p.Arg19Cys	missense	Exon 2 of 16	ENSP00000454963.1	H3BNQ7
ABAT	ENST00000566590.5	TSL:1	n.55C>T		non_coding_transcript_exon	Exon 2 of 15	ENSP00000455198.1	H3BP84

Frequencies

GnomAD3 genomes

AF:

0.00317

AC:

482

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0108

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00125

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.000935

AC:

220

AN:

235212

AF XY:

0.000668

show subpopulations

Gnomad AFR exome

AF:

0.0111

Gnomad AMR exome

AF:

0.000693

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000674

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000151

Gnomad OTH exome

AF:

0.000347

GnomAD4 exome

AF:

0.000416

AC:

604

AN:

1453524

Hom.:

Cov.:

AF XY:

0.000370

AC XY:

267

AN XY:

722210

show subpopulations

African (AFR)

AF:

0.0105

AC:

352

AN:

33440

American (AMR)

AF:

0.000595

AC:

AN:

43696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25886

East Asian (EAS)

AF:

0.000430

AC:

AN:

39578

South Asian (SAS)

AF:

0.000178

AC:

AN:

84454

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52172

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000127

AC:

141

AN:

1108396

Other (OTH)

AF:

0.000815

AC:

AN:

60142

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

132

165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00318

AC:

484

AN:

152232

Hom.:

Cov.:

AF XY:

0.00302

AC XY:

225

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0108

AC:

449

AN:

41536

American (AMR)

AF:

0.00124

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68022

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00109

Hom.:

Bravo

AF:

0.00340

ESP6500AA

AF:

0.0112

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00101

AC:

122

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Gamma-aminobutyric acid transaminase deficiency (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.062

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0085

MetaSVM

Benign

-0.42

MutationAssessor

Benign

2.0

PhyloP100

0.33

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.31

Sift

Benign

0.099

Sift4G

Uncertain

0.041

Polyphen

0.0020

Vest4

0.20

MVP

0.78

MPC

0.42

ClinPred

0.010

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.065

gMVP

0.47

Mutation Taster

=99/1

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

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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