NM_020686.6:c.*512G>A

Variant names:

• chr16-8781942-G-A
• rs3743798
• NM_020686.6:c.*512G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.307
• Publications: 9 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]

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

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 321104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
ABAT	NM_020686.6	c.*512G>A		3_prime_UTR_variant	Exon 16 of 16	ENST00000268251.13	NP_065737.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABAT	ENST00000268251.13	c.*512G>A		3_prime_UTR_variant	Exon 16 of 16	1	NM_020686.6	ENSP00000268251.8
ABAT	ENST00000396600.6	c.*512G>A		3_prime_UTR_variant	Exon 16 of 16	5		ENSP00000379845.2
TMEM186	ENST00000564869.1	n.32-498C>T		intron_variant	Intron 1 of 2	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

African (AFR) AF: 0.289 AC: 1251 AN: 4334

American (AMR) AF: 0.387 AC: 2384 AN: 6160

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 1805 AN: 3268

East Asian (EAS) AF: 0.450 AC: 2929 AN: 6506

South Asian (SAS) AF: 0.417 AC: 8792 AN: 21062

European-Finnish (FIN) AF: 0.496 AC: 2791 AN: 5622

Middle Eastern (MID) AF: 0.478 AC: 241 AN: 504

European-Non Finnish (NFE) AF: 0.479 AC: 37500 AN: 78252

Other (OTH) AF: 0.472 AC: 3188 AN: 6752

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

African (AFR) AF: 0.286 AC: 11852 AN: 41436

American (AMR) AF: 0.352 AC: 5373 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.542 AC: 1880 AN: 3468

East Asian (EAS) AF: 0.421 AC: 2168 AN: 5146

South Asian (SAS) AF: 0.400 AC: 1931 AN: 4822

European-Finnish (FIN) AF: 0.451 AC: 4776 AN: 10580

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.465 AC: 31557 AN: 67934

Other (OTH) AF: 0.395 AC: 835 AN: 2112

Alfa AF: 0.425 Hom.: 5634

Bravo AF: 0.389

Asia WGS AF: 0.404 AC: 1404 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gamma-aminobutyric acid transaminase deficiency Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.1
DANN	Benign	0.47
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

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: rs3743798; hg19: chr16-8875799;