rs183947905

chr16-8776494-A-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.1269+4A>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,610,344 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (6 hom., cov: 32)
  • Exomes 𝑓: 0.010 (109 hom.)
• Consequence: ABAT NM_020686.6 splice_donor_region, intron
• Scores: Splicing: ADA: 0.4075
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.540

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-8776494-A-C is Benign according to our data. Variant chr16-8776494-A-C is described in ClinVar as [Benign]. Clinvar id is 321087.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 = 0.00707 (1076/152274) while in subpopulation NFE AF= 0.012 (817/68002). AF 95% confidence interval is 0.0113. There are 6 homozygotes in gnomad4. There are 465 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABAT	NM_020686.6	c.1269+4A>C		splice_donor_region_variant, intron_variant		ENST00000268251.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABAT	ENST00000268251.13	c.1269+4A>C		splice_donor_region_variant, intron_variant		1	NM_020686.6	P1

Frequencies

GnomAD3 genomes AF: 0.00708 AC: 1078 AN: 152156 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00753 AC: 1802 AN: 239186 Hom.: 14 AF XY: 0.00761 AC XY: 990 AN XY: 130058

Gnomad AFR exome AF: 0.00158

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00255

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00550

Gnomad FIN exome AF: 0.00522

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.00871

GnomAD4 exome AF: 0.0104 AC: 15146 AN: 1458070 Hom.: 109 Cov.: 32 AF XY: 0.0104 AC XY: 7554 AN XY: 724972

Gnomad4 AFR exome AF: 0.00117

Gnomad4 AMR exome AF: 0.00338

Gnomad4 ASJ exome AF: 0.00261

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00619

Gnomad4 FIN exome AF: 0.00629

Gnomad4 NFE exome AF: 0.0121

Gnomad4 OTH exome AF: 0.00829

GnomAD4 genome AF: 0.00707 AC: 1076 AN: 152274 Hom.: 6 Cov.: 32 AF XY: 0.00624 AC XY: 465 AN XY: 74460

Gnomad4 AFR AF: 0.00209

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00643

Gnomad4 FIN AF: 0.00471

Gnomad4 NFE AF: 0.0120

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00974 Hom.: 3

Bravo AF: 0.00720

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ABAT: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 19, 2018	- -

Gamma-aminobutyric acid transaminase deficiency Benign:2

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	13
Dann	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.41
dbscSNV1_RF	Benign	0.41
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: rs183947905; hg19: chr16-8870351;