rs1063310

Variant names:

• chr5-170812108-C-A
• rs1063310
• NM_014211.3:c.1173C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014211.3(GABRP):​c.1173C>A​(p.Phe391Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,613,838 control chromosomes in the GnomAD database, including 45,146 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.25 (4821 hom., cov: 33)
  • Exomes 𝑓: 0.23 (40325 hom.)
• Consequence: GABRP NM_014211.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.715
• Publications: 28 publications found

Genes affected

GABRP (HGNC:4089): (gamma-aminobutyric acid type A receptor subunit pi) The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. The subunit encoded by this gene is expressed in several non-neuronal tissues including the uterus and ovaries. This subunit can assemble with known GABA A receptor subunits, and the presence of this subunit alters the sensitivity of recombinant receptors to modulatory agents such as pregnanolone. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016617179).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014211.3. 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
	GABRP	NM_014211.3	MANE Select	c.1173C>A	p.Phe391Leu	missense	Exon 10 of 10	NP_055026.1	O00591
	GABRP	NM_001291985.2		c.*115C>A		3_prime_UTR	Exon 9 of 9	NP_001278914.1	E7EWG0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRP	ENST00000265294.9	TSL:1 MANE Select	c.1173C>A	p.Phe391Leu	missense	Exon 10 of 10	ENSP00000265294.4	O00591
	GABRP	ENST00000518525.5	TSL:5	c.1173C>A	p.Phe391Leu	missense	Exon 11 of 11	ENSP00000430100.1	O00591
	GABRP	ENST00000862231.1		c.1173C>A	p.Phe391Leu	missense	Exon 10 of 10	ENSP00000532290.1

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37294 AN: 151954 Hom.: 4810 Cov.: 33

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.233

GnomAD2 exomes AF: 0.219 AC: 54992 AN: 251344 AF XY: 0.220

Gnomad AFR exome AF: 0.293

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.280

Gnomad FIN exome AF: 0.277

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.220

GnomAD4 exome AF: 0.232 AC: 338662 AN: 1461766 Hom.: 40325 Cov.: 34 AF XY: 0.229 AC XY: 166881 AN XY: 727186

African (AFR) AF: 0.289 AC: 9660 AN: 33474

American (AMR) AF: 0.122 AC: 5443 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 6593 AN: 26134

East Asian (EAS) AF: 0.277 AC: 10985 AN: 39694

South Asian (SAS) AF: 0.144 AC: 12404 AN: 86256

European-Finnish (FIN) AF: 0.272 AC: 14518 AN: 53416

Middle Eastern (MID) AF: 0.217 AC: 1249 AN: 5768

European-Non Finnish (NFE) AF: 0.237 AC: 264073 AN: 1111912

Other (OTH) AF: 0.227 AC: 13737 AN: 60392

GnomAD4 genome AF: 0.245 AC: 37333 AN: 152072 Hom.: 4821 Cov.: 33 AF XY: 0.245 AC XY: 18235 AN XY: 74334

African (AFR) AF: 0.292 AC: 12130 AN: 41472

American (AMR) AF: 0.171 AC: 2612 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 862 AN: 3470

East Asian (EAS) AF: 0.277 AC: 1429 AN: 5166

South Asian (SAS) AF: 0.138 AC: 667 AN: 4822

European-Finnish (FIN) AF: 0.285 AC: 3007 AN: 10568

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.237 AC: 16080 AN: 67976

Other (OTH) AF: 0.231 AC: 488 AN: 2116

Alfa AF: 0.240 Hom.: 17401

Bravo AF: 0.244

TwinsUK AF: 0.226 AC: 837

ALSPAC AF: 0.230 AC: 887

ESP6500AA AF: 0.304 AC: 1338

ESP6500EA AF: 0.244 AC: 2099

ExAC AF: 0.222 AC: 26949

Asia WGS AF: 0.188 AC: 655 AN: 3478

EpiCase AF: 0.238

EpiControl AF: 0.240

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.71
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.12
Sift	Benign	0.69	T
Sift4G	Benign	0.69	T
Polyphen		0.042	B
Vest4		0.080
MutPred		0.13		Gain of relative solvent accessibility (P = 0.0166)
MPC		0.14
ClinPred		0.0091	T
GERP RS		2.9
Varity_R		0.051
gMVP		0.35
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1063310; hg19: chr5-170239112; COSMIC: COSV54663293; COSMIC: COSV54663293;