4-47031698-C-A

Position:

• chr4-47031698-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000812.4(GABRB1):​c.47C>A​(p.Pro16His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P16S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GABRB1 NM_000812.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.90

Genes affected

GABRB1 (HGNC:4081): (gamma-aminobutyric acid type A receptor subunit beta1) The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. This gene encodes GABA A receptor, beta 1 subunit. It is mapped to chromosome 4p12 in a cluster comprised of genes encoding alpha 4, alpha 2 and gamma 1 subunits of the GABA A receptor. Alteration of this gene is implicated in the pathogenetics of schizophrenia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36872286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRB1	NM_000812.4	c.47C>A	p.Pro16His	missense_variant	1/9	ENST00000295454.8
GABRB1	XM_017007986.3	c.47C>A	p.Pro16His	missense_variant	1/5
GABRB1	XM_024453976.2	c.-19-216C>A		intron_variant
GABRB1	XM_024453977.2	c.-19-216C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRB1	ENST00000295454.8	c.47C>A	p.Pro16His	missense_variant	1/9	1	NM_000812.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461738 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 16, 2023

This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 16 of the GABRB1 protein (p.Pro16His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GABRB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1968949). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GABRB1 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.88	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.39	T
Polyphen		1.0	D
Vest4		0.25
MutPred		0.53		Gain of catalytic residue at P16 (P = 0.037);
MVP		0.74
MPC		0.027
ClinPred		0.93	D
GERP RS		4.5
Varity_R		0.28
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1021581518; hg19: chr4-47033715;