rs2228595

Positions:

• chr7-86786671-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_000840.3(GRM3):​c.879C>T​(p.Ala293=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0624 in 1,612,066 control chromosomes in the GnomAD database, including 3,624 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.051 (277 hom., cov: 32)
  • Exomes 𝑓: 0.064 (3347 hom.)
• Consequence: GRM3 NM_000840.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0260

Genes affected

GRM3 (HGNC:4595): (glutamate metabotropic receptor 3) L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The metabotropic glutamate receptors are a family of G protein-coupled receptors, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group I includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3 while Group III includes GRM4, GRM6, GRM7 and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities. [provided by RefSeq, Jul 2008]

GRM3-AS1 (HGNC:40264): (GRM3 antisense RNA 1)

LOC105375382 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP7: Synonymous conserved (PhyloP=-0.026 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0964 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM3	NM_000840.3	c.879C>T	p.Ala293=	synonymous_variant	3/6	ENST00000361669.7
LOC105375382	XR_007060408.1	n.511G>A		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM3	ENST00000361669.7	c.879C>T	p.Ala293=	synonymous_variant	3/6	1	NM_000840.3	P1
GRM3	ENST00000439827.1	c.879C>T	p.Ala293=	synonymous_variant	3/5	1
GRM3-AS1	ENST00000418031.2	n.982G>A		non_coding_transcript_exon_variant	3/4	3
GRM3	ENST00000454217.1	c.495C>T	p.Ala165=	synonymous_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0511 AC: 7786 AN: 152258 Hom.: 277 Cov.: 32

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0709

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.0620

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0459

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0619

Gnomad OTH AF: 0.0635

GnomAD3 exomes AF: 0.0681 AC: 16786 AN: 246570 Hom.: 698 AF XY: 0.0713 AC XY: 9545 AN XY: 133958

Gnomad AFR exome AF: 0.00951

Gnomad AMR exome AF: 0.0761

Gnomad ASJ exome AF: 0.146

Gnomad EAS exome AF: 0.0671

Gnomad SAS exome AF: 0.106

Gnomad FIN exome AF: 0.0486

Gnomad NFE exome AF: 0.0596

Gnomad OTH exome AF: 0.0760

GnomAD4 exome AF: 0.0635 AC: 92745 AN: 1459690 Hom.: 3347 Cov.: 33 AF XY: 0.0656 AC XY: 47656 AN XY: 726266

Gnomad4 AFR exome AF: 0.00965

Gnomad4 AMR exome AF: 0.0750

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.0564

Gnomad4 SAS exome AF: 0.106

Gnomad4 FIN exome AF: 0.0476

Gnomad4 NFE exome AF: 0.0597

Gnomad4 OTH exome AF: 0.0721

GnomAD4 genome AF: 0.0511 AC: 7785 AN: 152376 Hom.: 277 Cov.: 32 AF XY: 0.0524 AC XY: 3905 AN XY: 74508

Gnomad4 AFR AF: 0.0119

Gnomad4 AMR AF: 0.0709

Gnomad4 ASJ AF: 0.138

Gnomad4 EAS AF: 0.0618

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.0459

Gnomad4 NFE AF: 0.0619

Gnomad4 OTH AF: 0.0638

Alfa AF: 0.0633 Hom.: 393

Bravo AF: 0.0502

Asia WGS AF: 0.0610 AC: 213 AN: 3478

EpiCase AF: 0.0672

EpiControl AF: 0.0673

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.91

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: rs2228595; hg19: chr7-86415987; COSMIC: COSV64468992; COSMIC: COSV64468992;