16-8781379-C-T

Variant names:

• chr16-8781379-C-T
• rs61730647
• ENST00000569156.5:c.1511C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001386616.1(ABAT):​c.1511C>T​(p.Thr504Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 1,614,192 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T504T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (64 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (59 hom.)
• Consequence: ABAT NM_001386616.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.06
• Publications: 2 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 5 uncertain in NM_001386616.1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0018654168).
• BP6: Variant 16-8781379-C-T is Benign according to our data. Variant chr16-8781379-C-T is described in ClinVar as Benign. ClinVar VariationId is 321091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0527 is higher than 0.05.

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.1452C>T	p.His484His	synonymous	Exon 16 of 16	NP_065737.2
	ABAT	NM_001386616.1		c.1511C>T	p.Thr504Met	missense	Exon 16 of 16	NP_001373545.1	H3BNQ7
	ABAT	NM_001386609.1		c.1340C>T	p.Thr447Met	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.1511C>T	p.Thr504Met	missense	Exon 16 of 16	ENSP00000454963.1	H3BNQ7
	ABAT	ENST00000268251.13	TSL:1 MANE Select	c.1452C>T	p.His484His	synonymous	Exon 16 of 16	ENSP00000268251.8	P80404
	ABAT	ENST00000566590.5	TSL:1	n.*1192C>T		non_coding_transcript_exon	Exon 15 of 15	ENSP00000455198.1	H3BP84

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2232 AN: 152192 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.0515

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00407 AC: 1023 AN: 251490 AF XY: 0.00312

Gnomad AFR exome AF: 0.0565

Gnomad AMR exome AF: 0.00225

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00153 AC: 2242 AN: 1461882 Hom.: 59 Cov.: 34 AF XY: 0.00134 AC XY: 973 AN XY: 727240

African (AFR) AF: 0.0548 AC: 1834 AN: 33478

American (AMR) AF: 0.00268 AC: 120 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

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

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5768

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1112002

Other (OTH) AF: 0.00343 AC: 207 AN: 60396

GnomAD4 genome AF: 0.0147 AC: 2246 AN: 152310 Hom.: 64 Cov.: 32 AF XY: 0.0144 AC XY: 1069 AN XY: 74478

African (AFR) AF: 0.0517 AC: 2149 AN: 41572

American (AMR) AF: 0.00484 AC: 74 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68030

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.0117 Hom.: 32

Bravo AF: 0.0171

ESP6500AA AF: 0.0519 AC: 228

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00529 AC: 642

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Gamma-aminobutyric acid transaminase deficiency (2)
-	-	2	not provided (2)
-	-	1	ABAT-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	2.3
DANN	Benign	0.81
DEOGEN2	Benign	0.010	T
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0019	T
PhyloP100		-3.1
PROVEAN	Benign	-0.14	N
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Vest4		0.11
MVP		0.84
GERP RS		-6.1
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs61730647; hg19: chr16-8875236; COSMIC: COSV51625121;