NM_000840.3:c.1358T>A

Variant names:

• chr7-86838872-T-A
• rs763641866
• NM_000840.3:c.1358T>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000840.3(GRM3):​c.1358T>A​(p.Ile453Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,459,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: GRM3 NM_000840.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.14
• Publications: 0 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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13952509).
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000840.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM3	NM_000840.3	MANE Select	c.1358T>A	p.Ile453Lys	missense	Exon 4 of 6	NP_000831.2
	GRM3	NM_001363522.2		c.1325-11498T>A		intron	N/A	NP_001350451.1	Q14832-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM3	ENST00000361669.7	TSL:1 MANE Select	c.1358T>A	p.Ile453Lys	missense	Exon 4 of 6	ENSP00000355316.2	Q14832-1
	GRM3	ENST00000439827.1	TSL:1	c.1325-11498T>A		intron	N/A	ENSP00000398767.1	Q14832-2
	GRM3	ENST00000953115.1		c.1358T>A	p.Ile453Lys	missense	Exon 4 of 6	ENSP00000623174.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1459674 Hom.: 0 Cov.: 31 AF XY: 0.00000964 AC XY: 7 AN XY: 726188

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1110446

Other (OTH) AF: 0.0000166 AC: 1 AN: 60330

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	16
DANN	Benign	0.90
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.0046
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.51	N
PhyloP100		4.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.28
Sift	Benign	0.61	T
Sift4G	Benign	0.93	T
Polyphen		0.0020	B
Vest4		0.36
MutPred		0.55		Gain of disorder (P = 0.0014)
MVP		0.64
MPC		0.77
ClinPred		0.35	T
GERP RS		5.5
Varity_R		0.46
gMVP		0.64
Mutation Taster		=44/56	disease causing

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: rs763641866; hg19: chr7-86468188;