4-46041205-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_173536.4(GABRG1):c.1181T>C(p.Ile394Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000481 in 1,612,904 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00051 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (6 hom.)
• Consequence: GABRG1 NM_173536.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060000718).
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRG1	NM_173536.4	c.1181T>C	p.Ile394Thr	missense_variant	9/9	ENST00000295452.5
GABRG1	XM_017007990.2	c.794T>C	p.Ile265Thr	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRG1	ENST00000295452.5	c.1181T>C	p.Ile394Thr	missense_variant	9/9	1	NM_173536.4	P1

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 151966 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000659

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000755 AC: 189 AN: 250174 Hom.: 2 AF XY: 0.000784 AC XY: 106 AN XY: 135196

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000610

Gnomad ASJ exome AF: 0.00995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000488

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000478 AC: 698 AN: 1460820 Hom.: 6 Cov.: 31 AF XY: 0.000506 AC XY: 368 AN XY: 726726

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000516

Gnomad4 ASJ exome AF: 0.00870

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000335

Gnomad4 OTH exome AF: 0.000994

GnomAD4 genome AF: 0.000513 AC: 78 AN: 152084 Hom.: 1 Cov.: 32 AF XY: 0.000444 AC XY: 33 AN XY: 74336

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000658

Gnomad4 ASJ AF: 0.00951

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00102 Hom.: 3

Bravo AF: 0.000544

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000577 AC: 70

EpiCase AF: 0.000819

EpiControl AF: 0.000711

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 14, 2021

The c.1181T>C (p.I394T) alteration is located in exon 9 (coding exon 9) of the GABRG1 gene. This alteration results from a T to C substitution at nucleotide position 1181, causing the isoleucine (I) at amino acid position 394 to be replaced by a threonine (T). 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	0.15
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	14
Dann	Benign	0.29
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.13
Sift	Benign	0.47	T
Sift4G	Benign	0.49	T
Polyphen		0.13	B
Vest4		0.075
MVP		0.70
MPC		0.16
ClinPred		0.037	T
GERP RS		4.3
Varity_R		0.063
gMVP		0.36

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: rs149632298; hg19: chr4-46043222; COSMIC: COSV99778988;