dbSNP rs29230: GABBR1:p.Phe659Leu (chr6-29608616-A-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001470.4(GABBR1):c.1977T>G(p.Phe659Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GABBR1
NM_001470.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.33

Publications

55 publications found

Variant links:

Genes affected

GABBR1 (HGNC:4070): (gamma-aminobutyric acid type B receptor subunit 1) This gene encodes a receptor for gamma-aminobutyric acid (GABA), which is the main inhibitory neurotransmitter in the mammalian central nervous system. This receptor functions as a heterodimer with GABA(B) receptor 2. Defects in this gene may underlie brain disorders such as schizophrenia and epilepsy. Alternative splicing generates multiple transcript variants, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jan 2016]

GABBR1 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with language delay and variable cognitive abnormalities
Inheritance: AD Classification: MODERATE Submitted by: G2P

GABBR1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.811

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABBR1	NM_001470.4 link	c.1977T>G	p.Phe659Leu	missense_variant	Exon 16 of 23	ENST00000377034.9	NP_001461.1	Q9UBS5-1A0A1U9X7R0Q59HG8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABBR1	ENST00000377034.9 link	c.1977T>G	p.Phe659Leu	missense_variant	Exon 16 of 23	1	NM_001470.4	ENSP00000366233.4		Q9UBS5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000406

AC:

AN:

246210

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460546

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726588

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111886

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000846

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

.;.;.;D

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.83

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.81

D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

.;.;.;L

PhyloP100

2.3

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-4.1

D;D;D;D

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0060

D;D;D;D

Sift4G

Uncertain

0.015

D;D;D;D

Polyphen

0.95, 0.99

.;P;.;D

Vest4

0.66

MutPred

0.54

.;.;.;Loss of sheet (P = 0.0228);

MVP

0.86

MPC

2.0

ClinPred

0.97

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.68

gMVP

0.81

Mutation Taster

=28/72

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over