rs149271402

Positions:

• chr16-8768230-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020686.6(ABAT):​c.641T>C​(p.Met214Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00272 in 1,614,082 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (13 hom.)
• Consequence: ABAT NM_020686.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.90

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018425345).
• BP6: Variant 16-8768230-T-C is Benign according to our data. Variant chr16-8768230-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 283525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00219 (333/152268) while in subpopulation NFE AF= 0.00401 (273/68014). AF 95% confidence interval is 0.00362. There are 0 homozygotes in gnomad4. There are 162 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABAT	NM_020686.6	c.641T>C	p.Met214Thr	missense_variant	10/16	ENST00000268251.13	NP_065737.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABAT	ENST00000268251.13	c.641T>C	p.Met214Thr	missense_variant	10/16	1	NM_020686.6	ENSP00000268251.8

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 333 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00401

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00240 AC: 603 AN: 251488 Hom.: 5 AF XY: 0.00251 AC XY: 341 AN XY: 135918

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00268

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.00318

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00277 AC: 4055 AN: 1461814 Hom.: 13 Cov.: 31 AF XY: 0.00282 AC XY: 2051 AN XY: 727212

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00245

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00288

Gnomad4 FIN exome AF: 0.00341

Gnomad4 NFE exome AF: 0.00302

Gnomad4 OTH exome AF: 0.00248

GnomAD4 genome AF: 0.00219 AC: 333 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.00218 AC XY: 162 AN XY: 74458

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.00401

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00319 Hom.: 0

Bravo AF: 0.00177

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00251 AC: 305

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00251

EpiControl AF: 0.00184

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 26, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ABAT: BS2 -

Gamma-aminobutyric acid transaminase deficiency Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 28, 2015

- -

ABAT-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 04, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.19	T;T;.;T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	0.050
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	.;D;D;.;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.018	T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	-0.51	N;N;.;N;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.26	N;N;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.29	T;T;T;T;T
Sift4G	Benign	0.35	T;T;T;T;T
Polyphen		0.0	B;B;.;B;.
Vest4		0.67
MVP		0.82
MPC		0.36
ClinPred		0.021	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.78

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: rs149271402; hg19: chr16-8862087;