4-46041008-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_173536.4(GABRG1):c.1378G>A(p.Val460Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000962 in 1,611,766 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: GABRG1 NM_173536.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.745

Genes affected

GABRG1 (HGNC:4086): (gamma-aminobutyric acid type A receptor subunit gamma1) The protein encoded by this gene belongs to the ligand-gated ionic channel family. It is an integral membrane protein and plays an important role in inhibiting neurotransmission by binding to the benzodiazepine receptor and opening an integral chloride channel. This gene is clustered with three other family members on chromosome 4. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02319476).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRG1	NM_173536.4	c.1378G>A	p.Val460Ile	missense_variant	9/9	ENST00000295452.5
GABRG1	XM_017007990.2	c.991G>A	p.Val331Ile	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRG1	ENST00000295452.5	c.1378G>A	p.Val460Ile	missense_variant	9/9	1	NM_173536.4	P1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 151964 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000136 AC: 34 AN: 249336 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 134746

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000460

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000644 AC: 94 AN: 1459684 Hom.: 0 Cov.: 31 AF XY: 0.0000730 AC XY: 53 AN XY: 726096

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000523

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.000404 AC XY: 30 AN XY: 74334

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000669 Hom.: 0

Bravo AF: 0.000457

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000173 AC: 21

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2023

The c.1378G>A (p.V460I) alteration is located in exon 9 (coding exon 9) of the GABRG1 gene. This alteration results from a G to A substitution at nucleotide position 1378, causing the valine (V) at amino acid position 460 to be replaced by an isoleucine (I). 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	0.073
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	20
Dann	Benign	0.94
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.22	N
MutationTaster	Benign	0.91	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.22
Sift	Benign	0.37	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.085
MVP		0.67
MPC		0.10
ClinPred		0.038	T
GERP RS		4.5
Varity_R		0.069
gMVP		0.17

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

LitVar

Other links and lift over

dbSNP: rs201319051; hg19: chr4-46043025; COSMIC: COSV104600104;