16-8750498-G-A

Position:

chr16-8750498-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_020686.6(ABAT):c.275G>A(p.Arg92Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ABAT
NM_020686.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.96

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 links:

ABAT (HGNC:):

ABAT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.956

PP5

Variant 16-8750498-G-A is Pathogenic according to our data. Variant chr16-8750498-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 162036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-8750498-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABAT	NM_020686.6 linkuse as main transcript	c.275G>A	p.Arg92Gln	missense_variant	5/16	ENST00000268251.13	NP_065737.2	P80404X5D8S1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABAT	ENST00000268251.13 linkuse as main transcript	c.275G>A	p.Arg92Gln	missense_variant	5/16	1	NM_020686.6	ENSP00000268251.8		P80404

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Gamma-aminobutyric acid transaminase deficiency

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 92 of the ABAT protein (p.Arg92Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GABA transaminase deficiency (PMID: 20052547, 30617166). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162036). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ABAT protein function with a negative predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2010	- -
Pathogenic, criteria provided, single submitter	research	Bonnen Lab, Baylor College of Medicine	Jan 01, 2014	clinical and in vitro studies -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 07, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.29

T;T;.;T;T

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

.;D;D;.;D

M_CAP

Benign

0.063

MetaRNN

Pathogenic

0.96

D;D;D;D;D

MetaSVM

Uncertain

0.29

MutationAssessor

Uncertain

2.3

M;M;.;M;.

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.0

N;N;N;N;N

REVEL

Pathogenic

0.74

Sift

Benign

0.21

T;T;T;T;T

Sift4G

Benign

0.38

T;T;T;T;T

Polyphen

1.0

D;D;.;D;.

Vest4

0.92

MutPred

0.86

Gain of phosphorylation at Y97 (P = 0.2414);Gain of phosphorylation at Y97 (P = 0.2414);.;Gain of phosphorylation at Y97 (P = 0.2414);Gain of phosphorylation at Y97 (P = 0.2414);

MVP

0.91

MPC

0.47

ClinPred

0.95

GERP RS

5.9

Varity_R

0.43

gMVP

0.79

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over