7-86838872-T-A

Position:

• chr7-86838872-T-A

Variant summary

Our verdict is Likely benign. Variant got -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. 13/21 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

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 Likely_benign. Variant got -6 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM3	NM_000840.3	c.1358T>A	p.Ile453Lys	missense_variant	4/6	ENST00000361669.7	NP_000831.2
GRM3	XM_047420268.1	c.1358T>A	p.Ile453Lys	missense_variant	5/7		XP_047276224.1
GRM3	NM_001363522.2	c.1325-11498T>A		intron_variant			NP_001350451.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRM3	ENST00000361669.7	c.1358T>A	p.Ile453Lys	missense_variant	4/6	1	NM_000840.3	ENSP00000355316.2
GRM3	ENST00000439827.1	c.1325-11498T>A		intron_variant		1		ENSP00000398767.1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2024

The c.1358T>A (p.I453K) alteration is located in exon 4 (coding exon 3) of the GRM3 gene. This alteration results from a T to A substitution at nucleotide position 1358, causing the isoleucine (I) at amino acid position 453 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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
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

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: rs763641866; hg19: chr7-86468188;