Genetic Variant NM_020686.6:c.1435G>T (chr16-8781362-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_020686.6(ABAT):c.1435G>T(p.Val479Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

ABAT
NM_020686.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.70

Publications

0 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 links:

TMEM186 (HGNC:24530): (transmembrane protein 186) This gene encodes a potential transmembrane protein. [provided by RefSeq, Dec 2012]

TMEM186 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_020686.6

PM2

Very rare variant in population databases, with high coverage;

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.1435G>T	p.Val479Phe	missense	Exon 16 of 16	NP_065737.2
ABAT	NM_001386615.1		c.1531G>T	p.Val511Phe	missense	Exon 17 of 17	NP_001373544.1
ABAT	NM_001386616.1		c.1494G>T	p.Trp498Cys	missense	Exon 16 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.1435G>T	p.Val479Phe	missense	Exon 16 of 16	ENSP00000268251.8	P80404
ABAT	ENST00000569156.5	TSL:1	c.1494G>T	p.Trp498Cys	missense	Exon 16 of 16	ENSP00000454963.1	H3BNQ7
ABAT	ENST00000566590.5	TSL:1	n.*1175G>T		non_coding_transcript_exon	Exon 15 of 15	ENSP00000455198.1	H3BP84

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Gamma-aminobutyric acid transaminase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Uncertain

0.039

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.093

MetaRNN

Uncertain

0.53

MetaSVM

Benign

-0.92

MutationAssessor

Pathogenic

3.1

PhyloP100

2.7

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.26

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0060

Polyphen

0.96

Vest4

0.52

MutPred

0.58

Gain of catalytic residue at V479 (P = 0.0533)

MVP

0.42

MPC

0.77

ClinPred

0.98

GERP RS

3.4

Varity_R

0.86

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over