5-170805773-G-A

Position:

• chr5-170805773-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014211.3(GABRP):​c.599G>A​(p.Arg200His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,614,152 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (47 hom.)
• Consequence: GABRP NM_014211.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.77

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006946802).
• BP6: Variant 5-170805773-G-A is Benign according to our data. Variant chr5-170805773-G-A is described in ClinVar as [Benign]. Clinvar id is 785153.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0115 (1753/152284) while in subpopulation AFR AF= 0.0393 (1632/41558). AF 95% confidence interval is 0.0377. There are 37 homozygotes in gnomad4. There are 868 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRP	NM_014211.3	c.599G>A	p.Arg200His	missense_variant	7/10	ENST00000265294.9	NP_055026.1
GABRP	NM_001291985.2	c.599G>A	p.Arg200His	missense_variant	7/9		NP_001278914.1
GABRP	XM_024446012.2	c.599G>A	p.Arg200His	missense_variant	7/10		XP_024301780.1
GABRP	XM_005265872.2	c.362G>A	p.Arg121His	missense_variant	5/8		XP_005265929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRP	ENST00000265294.9	c.599G>A	p.Arg200His	missense_variant	7/10	1	NM_014211.3	ENSP00000265294	P1

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1739 AN: 152166 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0390

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00577

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0119

GnomAD3 exomes AF: 0.00305 AC: 766 AN: 251424 Hom.: 18 AF XY: 0.00222 AC XY: 301 AN XY: 135874

Gnomad AFR exome AF: 0.0425

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00126 AC: 1839 AN: 1461868 Hom.: 47 Cov.: 31 AF XY: 0.00109 AC XY: 793 AN XY: 727240

Gnomad4 AFR exome AF: 0.0443

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.0115 AC: 1753 AN: 152284 Hom.: 37 Cov.: 32 AF XY: 0.0117 AC XY: 868 AN XY: 74474

Gnomad4 AFR AF: 0.0393

Gnomad4 AMR AF: 0.00576

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00264 Hom.: 9

Bravo AF: 0.0136

ESP6500AA AF: 0.0404 AC: 178

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00372 AC: 452

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	24
DANN	Benign	0.85
DEOGEN2	Benign	0.12	T;T;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	0.046
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.94	.;D;D;D
MetaRNN	Benign	0.0069	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.20	N;N;.;.
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.060	N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.37	T;T;T;T
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.17	B;B;B;.
Vest4		0.30
MVP		0.85
MPC		0.16
ClinPred		0.012	T
GERP RS		5.1
Varity_R		0.065
gMVP		0.26

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: rs112704076; hg19: chr5-170232777; COSMIC: COSV54664724; COSMIC: COSV54664724;