4-47031724-G-T

Position:

• chr4-47031724-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000812.4(GABRB1):​c.73G>T​(p.Ala25Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,814 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GABRB1 NM_000812.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.68

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19267255).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRB1	NM_000812.4	c.73G>T	p.Ala25Ser	missense_variant	1/9	ENST00000295454.8	NP_000803.2
GABRB1	XM_017007986.3	c.73G>T	p.Ala25Ser	missense_variant	1/5		XP_016863475.1
GABRB1	XM_024453976.2	c.-19-190G>T		intron_variant			XP_024309744.1
GABRB1	XM_024453977.2	c.-19-190G>T		intron_variant			XP_024309745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRB1	ENST00000295454.8	c.73G>T	p.Ala25Ser	missense_variant	1/9	1	NM_000812.4	ENSP00000295454	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460814 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726838

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

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

Labcorp Genetics (formerly Invitae), Labcorp

May 01, 2023

This variant is not present in population databases (gnomAD no frequency). 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. 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 not expected to disrupt GABRB1 protein function. This variant has not been reported in the literature in individuals affected with GABRB1-related conditions. This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 25 of the GABRB1 protein (p.Ala25Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.090
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	0.66	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.25	N
REVEL	Uncertain	0.36
Sift	Benign	0.19	T
Sift4G	Benign	0.76	T
Polyphen		0.13	B
Vest4		0.27
MutPred		0.48		Gain of disorder (P = 0.0274);
MVP		0.50
MPC		0.016
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.21
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-47033741;