rs3743798

chr16-8781942-G-Achr16-8781942-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_020686.6(ABAT):c.*512G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 284,430 control chromosomes in the GnomAD database, including 26,244 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.40 (12520 hom., cov: 31)
  • Exomes 𝑓: 0.46 (13724 hom.)
• Consequence: ABAT NM_020686.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.307

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]

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

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 16-8781942-G-A is Benign according to our data. Variant chr16-8781942-G-A is described in ClinVar as [Benign]. Clinvar id is 321104.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABAT	NM_020686.6	c.*512G>A		3_prime_UTR_variant	16/16	ENST00000268251.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABAT	ENST00000268251.13	c.*512G>A		3_prime_UTR_variant	16/16	1	NM_020686.6	P1
ABAT	ENST00000396600.6	c.*512G>A		3_prime_UTR_variant	16/16	5		P1
TMEM186	ENST00000564869.1	n.32-498C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60748 AN: 151852 Hom.: 12517 Cov.: 31

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.290

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.542

Gnomad EAS AF: 0.421

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.451

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.465

Gnomad OTH AF: 0.396

GnomAD4 exome AF: 0.460 AC: 60881 AN: 132460 Hom.: 13724 Cov.: 0 AF XY: 0.454 AC XY: 32050 AN XY: 70548

Gnomad4 AFR exome AF: 0.289

Gnomad4 AMR exome AF: 0.387

Gnomad4 ASJ exome AF: 0.552

Gnomad4 EAS exome AF: 0.450

Gnomad4 SAS exome AF: 0.417

Gnomad4 FIN exome AF: 0.496

Gnomad4 NFE exome AF: 0.479

Gnomad4 OTH exome AF: 0.472

GnomAD4 genome AF: 0.400 AC: 60771 AN: 151970 Hom.: 12520 Cov.: 31 AF XY: 0.395 AC XY: 29323 AN XY: 74280

Gnomad4 AFR AF: 0.286

Gnomad4 AMR AF: 0.352

Gnomad4 ASJ AF: 0.542

Gnomad4 EAS AF: 0.421

Gnomad4 SAS AF: 0.400

Gnomad4 FIN AF: 0.451

Gnomad4 NFE AF: 0.465

Gnomad4 OTH AF: 0.395

Alfa AF: 0.425 Hom.: 3603

Bravo AF: 0.389

Asia WGS AF: 0.404 AC: 1404 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gamma-aminobutyric acid transaminase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	3.1
Dann	Benign	0.47

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: rs3743798; hg19: chr16-8875799;