5-170812108-C-A

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. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRP	NM_014211.3	c.1173C>A	p.Phe391Leu	missense_variant	Exon 10 of 10	ENST00000265294.9	NP_055026.1
GABRP	XM_024446012.2	c.1173C>A	p.Phe391Leu	missense_variant	Exon 10 of 10		XP_024301780.1
GABRP	XM_005265872.2	c.936C>A	p.Phe312Leu	missense_variant	Exon 8 of 8		XP_005265929.1
GABRP	NM_001291985.2	c.*115C>A		3_prime_UTR_variant	Exon 9 of 9		NP_001278914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRP	ENST00000265294.9	c.1173C>A	p.Phe391Leu	missense_variant	Exon 10 of 10	1	NM_014211.3	ENSP00000265294.4
GABRP	ENST00000518525.5	c.1173C>A	p.Phe391Leu	missense_variant	Exon 11 of 11	5		ENSP00000430100.1
GABRP	ENST00000519385.5	c.*115C>A		3_prime_UTR_variant	Exon 9 of 9	2		ENSP00000430727.1

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

Gnomad4 AFR exome AF: 0.289 AC: 9660 AN: 33474

Gnomad4 AMR exome AF: 0.122 AC: 5443 AN: 44720

Gnomad4 ASJ exome AF: 0.252 AC: 6593 AN: 26134

Gnomad4 EAS exome AF: 0.277 AC: 10985 AN: 39694

Gnomad4 SAS exome AF: 0.144 AC: 12404 AN: 86256

Gnomad4 FIN exome AF: 0.272 AC: 14518 AN: 53416

Gnomad4 NFE exome AF: 0.237 AC: 264073 AN: 1111912

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.292 AC: 0.292486 AN: 0.292486

Gnomad4 AMR AF: 0.171 AC: 0.170965 AN: 0.170965

Gnomad4 ASJ AF: 0.248 AC: 0.248415 AN: 0.248415

Gnomad4 EAS AF: 0.277 AC: 0.276616 AN: 0.276616

Gnomad4 SAS AF: 0.138 AC: 0.138324 AN: 0.138324

Gnomad4 FIN AF: 0.285 AC: 0.284538 AN: 0.284538

Gnomad4 NFE AF: 0.237 AC: 0.236554 AN: 0.236554

Gnomad4 OTH AF: 0.231 AC: 0.230624 AN: 0.230624

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 v4.3

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;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;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.11	N;N
REVEL	Benign	0.12
Sift	Benign	0.69	T;T
Sift4G	Benign	0.69	T;T
Polyphen		0.042	B;B
Vest4		0.080
MutPred		0.13		Gain of relative solvent accessibility (P = 0.0166);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

Publications

LitVar

Other links and lift over

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