NM_000812.4:c.508T>A

Variant names:

• chr4-47320173-T-A
• rs4482737
• NM_000812.4:c.508T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000812.4(GABRB1):​c.508T>A​(p.Leu170Met) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L170L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GABRB1 NM_000812.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.23
• Publications: 16 publications found

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]

GABRB1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 45

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

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, 0.777

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000812.4. 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
	GABRB1	NM_000812.4	MANE Select	c.508T>A	p.Leu170Met	missense	Exon 5 of 9	NP_000803.2	X5DNL6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB1	ENST00000295454.8	TSL:1 MANE Select	c.508T>A	p.Leu170Met	missense	Exon 5 of 9	ENSP00000295454.3	P18505-1
	GABRB1	ENST00000510909.1	TSL:4	n.*176T>A		non_coding_transcript_exon	Exon 4 of 5	ENSP00000426766.1	P18505-2
	GABRB1	ENST00000510909.1	TSL:4	n.*176T>A		3_prime_UTR	Exon 4 of 5	ENSP00000426766.1	P18505-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1455648 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 724616

African (AFR) AF: 0.00 AC: 0 AN: 33346

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106214

Other (OTH) AF: 0.00 AC: 0 AN: 60246

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.030
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.2
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.52
Sift	Benign	0.051	T
Sift4G	Benign	0.43	T
Polyphen		1.0	D
Vest4		0.56
MutPred		0.77		Loss of sheet (P = 0.1158)
MVP		0.93
MPC		2.5
ClinPred		0.90	D
GERP RS		5.2
Varity_R		0.12
gMVP		0.64
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs4482737; hg19: chr4-47322190;