rs150914629

Variant names:

• chr16-8776407-A-G
• rs150914629
• NM_020686.6:c.1186A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_020686.6(ABAT):​c.1186A>G​(p.Ile396Val) variant causes a missense change. The variant allele was found at a frequency of 0.000204 in 1,614,202 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: ABAT NM_020686.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 4.48
• Publications: 2 publications found

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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0107753575).
• BP6: Variant 16-8776407-A-G is Benign according to our data. Variant chr16-8776407-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 585340.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00109 (166/152312) while in subpopulation AFR AF = 0.00382 (159/41570). AF 95% confidence interval is 0.00334. There are 1 homozygotes in GnomAd4. There are 91 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABAT	NM_020686.6	MANE Select	c.1186A>G	p.Ile396Val	missense	Exon 14 of 16	NP_065737.2
	ABAT	NM_001386615.1		c.1282A>G	p.Ile428Val	missense	Exon 15 of 17	NP_001373544.1
	ABAT	NM_001386616.1		c.1186A>G	p.Ile396Val	missense	Exon 14 of 16	NP_001373545.1	H3BNQ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABAT	ENST00000268251.13	TSL:1 MANE Select	c.1186A>G	p.Ile396Val	missense	Exon 14 of 16	ENSP00000268251.8	P80404
	ABAT	ENST00000569156.5	TSL:1	c.1186A>G	p.Ile396Val	missense	Exon 14 of 16	ENSP00000454963.1	H3BNQ7
	ABAT	ENST00000566590.5	TSL:1	n.*926A>G		non_coding_transcript_exon	Exon 13 of 15	ENSP00000455198.1	H3BP84

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152194 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00384

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000955

GnomAD2 exomes AF: 0.000302 AC: 76 AN: 251464 AF XY: 0.000235

Gnomad AFR exome AF: 0.00424

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000111 AC: 163 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.0000880 AC XY: 64 AN XY: 727246

African (AFR) AF: 0.00409 AC: 137 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112008

Other (OTH) AF: 0.000182 AC: 11 AN: 60396

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152312 Hom.: 1 Cov.: 32 AF XY: 0.00122 AC XY: 91 AN XY: 74484

African (AFR) AF: 0.00382 AC: 159 AN: 41570

American (AMR) AF: 0.000261 AC: 4 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000470 Hom.: 0

Bravo AF: 0.00115

ESP6500AA AF: 0.00523 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000321 AC: 39

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	ABAT-related disorder (1)
-	-	1	Gamma-aminobutyric acid transaminase deficiency (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.045
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.54	N
REVEL	Uncertain	0.30
Sift	Benign	0.29	T
Sift4G	Benign	0.33	T
Polyphen		0.0010	B
Vest4		0.47
MVP		0.65
MPC		0.27
ClinPred		0.044	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.087
gMVP		0.74
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs150914629; hg19: chr16-8870264;