7-86838938-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_000840.3(GRM3):c.1424G>A(p.Gly475Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,613,628 control chromosomes in the GnomAD database, including 137 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0092 (12 hom., cov: 32)
  • Exomes 𝑓: 0.012 (125 hom.)
• Consequence: GRM3 NM_000840.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.46

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GRM3
• BP4: Computational evidence support a benign effect (MetaRNN=0.007987589).
• BP6: Variant 7-86838938-G-A is Benign according to our data. Variant chr7-86838938-G-A is described in ClinVar as [Benign]. Clinvar id is 2657657.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 1398 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM3	NM_000840.3	c.1424G>A	p.Gly475Asp	missense_variant	4/6	ENST00000361669.7
GRM3	XM_047420268.1	c.1424G>A	p.Gly475Asp	missense_variant	5/7
GRM3	NM_001363522.2	c.1325-11432G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM3	ENST00000361669.7	c.1424G>A	p.Gly475Asp	missense_variant	4/6	1	NM_000840.3	P1
GRM3	ENST00000439827.1	c.1325-11432G>A		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.00919 AC: 1398 AN: 152200 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00933

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0102 AC: 2559 AN: 251210 Hom.: 17 AF XY: 0.0108 AC XY: 1461 AN XY: 135774

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00885

Gnomad ASJ exome AF: 0.0172

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0114

Gnomad FIN exome AF: 0.00356

Gnomad NFE exome AF: 0.0135

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.0120 AC: 17552 AN: 1461310 Hom.: 125 Cov.: 32 AF XY: 0.0119 AC XY: 8681 AN XY: 726974

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.00977

Gnomad4 ASJ exome AF: 0.0165

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0111

Gnomad4 FIN exome AF: 0.00361

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.0130

GnomAD4 genome AF: 0.00917 AC: 1397 AN: 152318 Hom.: 12 Cov.: 32 AF XY: 0.00881 AC XY: 656 AN XY: 74468

Gnomad4 AFR AF: 0.00219

Gnomad4 AMR AF: 0.0143

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00934

Gnomad4 FIN AF: 0.00311

Gnomad4 NFE AF: 0.0130

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0121 Hom.: 27

Bravo AF: 0.0102

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.0169 AC: 65

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.0137 AC: 118

ExAC AF: 0.0106 AC: 1286

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0157

EpiControl AF: 0.0157

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

CeGaT Center for Human Genetics Tuebingen

May 01, 2022

GRM3: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	17
Dann	Benign	0.97
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.097
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.95	L
MutationTaster	Benign	0.98	D;D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.44	N
REVEL	Uncertain	0.32
Sift	Benign	0.31	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.073
MPC		0.53
ClinPred		0.0085	T
GERP RS		5.9
Varity_R		0.33
gMVP		0.54

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: rs17161026; hg19: chr7-86468254; COSMIC: COSV64479811;