3-98007903-A-T

Variant names:

• chr3-98007903-A-T
• rs832032
• NM_001105580.3:c.615T>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001105580.3(GABRR3):​c.615T>A​(p.Tyr205*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,554,836 control chromosomes in the GnomAD database, including 32,408 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely risk allele (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.21 (3692 hom., cov: 32)
  • Exomes 𝑓: 0.20 (28716 hom.)
• Consequence: GABRR3 NM_001105580.3 stop_gained, splice_region
• Clinical Significance: Likely risk allele no assertion criteria provided P:1
• Conservation: PhyloP100: 2.75
• Publications: 34 publications found

Genes affected

GABRR3 (HGNC:17969): (gamma-aminobutyric acid type A receptor subunit rho3) The neurotransmitter gamma-aminobutyric acid (GABA) functions in the central nervous system to regulate synaptic transmission of neurons. This gene encodes one of three related subunits, which combine as homo- or hetero-pentamers to form GABA(C) receptors. In humans, some individuals contain a single-base polymorphism (dbSNP rs832032) that is predicted to inactivate the gene product. [provided by RefSeq, Jan 2012]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRR3	NM_001105580.3	c.615T>A	p.Tyr205*	stop_gained, splice_region_variant	Exon 7 of 10	ENST00000472788.6	NP_001099050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRR3	ENST00000472788.6	c.615T>A	p.Tyr205*	stop_gained, splice_region_variant	Exon 7 of 10	5	NM_001105580.3	ENSP00000420790.1
GABRR3	ENST00000470589.1	n.501+4441T>A		intron_variant	Intron 5 of 5	1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32178 AN: 152034 Hom.: 3686 Cov.: 32

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.0104

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.290

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.214

GnomAD4 exome AF: 0.197 AC: 276501 AN: 1402684 Hom.: 28716 Cov.: 32 AF XY: 0.198 AC XY: 136892 AN XY: 692680

African (AFR) AF: 0.285 AC: 8990 AN: 31540

American (AMR) AF: 0.128 AC: 4281 AN: 33546

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 5465 AN: 24830

East Asian (EAS) AF: 0.00599 AC: 225 AN: 37588

South Asian (SAS) AF: 0.210 AC: 16350 AN: 77688

European-Finnish (FIN) AF: 0.156 AC: 7905 AN: 50626

Middle Eastern (MID) AF: 0.267 AC: 1511 AN: 5660

European-Non Finnish (NFE) AF: 0.203 AC: 220348 AN: 1082964

Other (OTH) AF: 0.196 AC: 11426 AN: 58242

GnomAD4 genome AF: 0.212 AC: 32213 AN: 152152 Hom.: 3692 Cov.: 32 AF XY: 0.207 AC XY: 15370 AN XY: 74404

African (AFR) AF: 0.276 AC: 11457 AN: 41482

American (AMR) AF: 0.180 AC: 2751 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 742 AN: 3462

East Asian (EAS) AF: 0.0106 AC: 55 AN: 5182

South Asian (SAS) AF: 0.195 AC: 941 AN: 4828

European-Finnish (FIN) AF: 0.152 AC: 1614 AN: 10602

Middle Eastern (MID) AF: 0.295 AC: 86 AN: 292

European-Non Finnish (NFE) AF: 0.206 AC: 14027 AN: 67988

Other (OTH) AF: 0.212 AC: 448 AN: 2112

Alfa AF: 0.204 Hom.: 2539

Bravo AF: 0.216

ClinVar

Significance: Likely risk allele

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Restless legs Pathogenic:1

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Eleanor M. Freitas Health Laboratory

Significance: Likely risk allele

Review Status: no assertion criteria provided

Collection Method: research

The variant rs832032 (Allele T) in women but not men, was found to be in statistically significant association (P-value: 0.002; corrected p-value: 0.014; 95% CI) with an increased risk (OR :1.80 ;CI 1.21–2.67; 95% CI: ) of Restless Leg Syndrome (RLS),. This association was observed in a robust study that compared healthy controls (n = 205) vs. affected patients with RLS (n = 230). The study was underpinned by rigorous inclusion & exclusion criteria, as well as, meticulous and comprehensive data analysis methods and data analysis. There is sufficient statistical power in the overall study and in the T-allele gender-specific sub-group. In our Power analysis conducted specifically for this sub-group, we determined an effect size of 0.210, with an alpha error probability of 0.05 and a power (1-β) of 0.80, using a chi-square test for goodness-of-fit (contingency tables). The required sample size for the sub-group was calculated to be 291 and the actual power obtained was 0.8002. This indicates the sub-group analysis was sufficiently powered, alongside an adequate sample size and statistically significant association which supports the classification of this variant as a "Likely Risk Allele" for RLS. Nevertheless, further well-powered, high-quality genotype association studies, with large or sufficient population sizes and better diversification of ethnic groups for full population representation, would be needed to confirm the risk association as definitive, or as an "established risk allele", as opposed to "likely risk allele". -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	37
PhyloP100		2.7
Vest4		0.35

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs832032; hg19: chr3-97726747;