3-98007903-A-T

Position:

• chr3-98007903-A-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP5 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

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]

GABRR3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP5: Variant 3-98007903-A-T is Pathogenic according to our data. Variant chr3-98007903-A-T is described in ClinVar as [Likely_risk_allele]. Clinvar id is 3338473.Status of the report is no_assertion_criteria_provided, 0 stars. We mark this variant Likely_pathogenic, oryginal submission is: [Likely_risk_allele].
• 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/exons	MANE	Protein	UniProt
GABRR3	NM_001105580.3	c.615T>A	p.Tyr205*	stop_gained, splice_region_variant	7/10	ENST00000472788.6	NP_001099050.1

Ensembl

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

Gnomad4 AFR exome AF: 0.285

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.220

Gnomad4 EAS exome AF: 0.00599

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.156

Gnomad4 NFE exome AF: 0.203

Gnomad4 OTH exome AF: 0.196

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

Gnomad4 AFR AF: 0.276

Gnomad4 AMR AF: 0.180

Gnomad4 ASJ AF: 0.214

Gnomad4 EAS AF: 0.0106

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.152

Gnomad4 NFE AF: 0.206

Gnomad4 OTH AF: 0.212

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

Likely risk allele, no assertion criteria provided

research

Eleanor M. Freitas Health Laboratory

-

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
Vest4		0.35

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs832032; hg19: chr3-97726747;