rs2060432508

Variant names:

• chr16-8781316-G-A
• rs2060432508
• ENST00000569156.5:c.1448G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-8781316-G-A
• chr16-8781316-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 4P and 3B. PM1 PM2 BP4_Moderate BP6

The NM_001386616.1(ABAT):​c.1448G>A​(p.Cys483Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ABAT NM_001386616.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.0840
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_001386616.1
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13013354).
• BP6: Variant 16-8781316-G-A is Benign according to our data. Variant chr16-8781316-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 887491.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386616.1. 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.1389G>A	p.Val463Val	synonymous	Exon 16 of 16	NP_065737.2
	ABAT	NM_001386616.1		c.1448G>A	p.Cys483Tyr	missense	Exon 16 of 16	NP_001373545.1	H3BNQ7
	ABAT	NM_001386609.1		c.1277G>A	p.Cys426Tyr	missense	Exon 15 of 15	NP_001373538.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABAT	ENST00000569156.5	TSL:1	c.1448G>A	p.Cys483Tyr	missense	Exon 16 of 16	ENSP00000454963.1	H3BNQ7
	ABAT	ENST00000268251.13	TSL:1 MANE Select	c.1389G>A	p.Val463Val	synonymous	Exon 16 of 16	ENSP00000268251.8	P80404
	ABAT	ENST00000566590.5	TSL:1	n.*1129G>A		non_coding_transcript_exon	Exon 15 of 15	ENSP00000455198.1	H3BP84

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461834 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111978

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Gamma-aminobutyric acid transaminase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	16
DANN	Benign	0.84
DEOGEN2	Benign	0.0087	T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.13	T
PhyloP100		0.084
PROVEAN	Benign	1.6	N
Sift	Pathogenic	0.0	D
Vest4		0.19
MVP		0.90
GERP RS		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2060432508; hg19: chr16-8875173;