rs2228595

Variant names:

• chr7-86786671-C-T
• rs2228595
• NM_000840.3:c.879C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_000840.3(GRM3):​c.879C>T​(p.Ala293Ala) 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
• Publications: 20 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
GRM3	NM_000840.3	c.879C>T	p.Ala293Ala	synonymous_variant	Exon 3 of 6	ENST00000361669.7	NP_000831.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM3	ENST00000361669.7	c.879C>T	p.Ala293Ala	synonymous_variant	Exon 3 of 6	1	NM_000840.3	ENSP00000355316.2

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

GnomAD2 exomes AF: 0.0681 AC: 16786 AN: 246570 AF XY: 0.0713

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 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

African (AFR) AF: 0.00965 AC: 323 AN: 33476

American (AMR) AF: 0.0750 AC: 3351 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 3767 AN: 26104

East Asian (EAS) AF: 0.0564 AC: 2237 AN: 39696

South Asian (SAS) AF: 0.106 AC: 9177 AN: 86226

European-Finnish (FIN) AF: 0.0476 AC: 2450 AN: 51502

Middle Eastern (MID) AF: 0.117 AC: 675 AN: 5768

European-Non Finnish (NFE) AF: 0.0597 AC: 66413 AN: 1111860

Other (OTH) AF: 0.0721 AC: 4352 AN: 60362

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

African (AFR) AF: 0.0119 AC: 494 AN: 41594

American (AMR) AF: 0.0709 AC: 1086 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 480 AN: 3472

East Asian (EAS) AF: 0.0618 AC: 320 AN: 5180

South Asian (SAS) AF: 0.104 AC: 502 AN: 4832

European-Finnish (FIN) AF: 0.0459 AC: 488 AN: 10624

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0619 AC: 4213 AN: 68038

Other (OTH) AF: 0.0638 AC: 135 AN: 2116

Alfa AF: 0.0612 Hom.: 454

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
PhyloP100		-0.026
Mutation Taster		=100/0	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: rs2228595; hg19: chr7-86415987; COSMIC: COSV64468992; COSMIC: COSV64468992;