chr4-47031703-A-T

Variant names:

• chr4-47031703-A-T
• NM_000812.4:c.52A>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.52A>T​(p.Met18Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. M18V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRB1 NM_000812.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.73

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=0.11496365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB1	NM_000812.4	c.52A>T	p.Met18Leu	missense_variant	Exon 1 of 9	ENST00000295454.8	NP_000803.2
GABRB1	XM_017007986.3	c.52A>T	p.Met18Leu	missense_variant	Exon 1 of 5		XP_016863475.1
GABRB1	XM_024453976.2	c.-19-211A>T		intron_variant	Intron 1 of 8		XP_024309744.1
GABRB1	XM_024453977.2	c.-19-211A>T		intron_variant	Intron 2 of 9		XP_024309745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB1	ENST00000295454.8	c.52A>T	p.Met18Leu	missense_variant	Exon 1 of 9	1	NM_000812.4	ENSP00000295454.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.52A>T (p.M18L) alteration is located in exon 1 (coding exon 1) of the GABRB1 gene. This alteration results from a A to T substitution at nucleotide position 52, causing the methionine (M) at amino acid position 18 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Benign	0.80
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.20	N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.22
Sift	Benign	0.68	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.49		Loss of helix (P = 0.2271);
MVP		0.33
MPC		0.016
ClinPred		0.061	T
GERP RS		3.3
Varity_R		0.11
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr4-47033720;