7-86838980-C-T

Variant names:

• chr7-86838980-C-T
• rs536332070
• NM_000840.3:c.1466C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000840.3(GRM3):​c.1466C>T​(p.Thr489Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T489N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GRM3 NM_000840.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.954

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=0.21608853).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM3	NM_000840.3	c.1466C>T	p.Thr489Ile	missense_variant	Exon 4 of 6	ENST00000361669.7	NP_000831.2
GRM3	XM_047420268.1	c.1466C>T	p.Thr489Ile	missense_variant	Exon 5 of 7		XP_047276224.1
GRM3	NM_001363522.2	c.1325-11390C>T		intron_variant	Intron 3 of 4		NP_001350451.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM3	ENST00000361669.7	c.1466C>T	p.Thr489Ile	missense_variant	Exon 4 of 6	1	NM_000840.3	ENSP00000355316.2
GRM3	ENST00000439827.1	c.1325-11390C>T		intron_variant	Intron 3 of 4	1		ENSP00000398767.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461784 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74308

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.23
Sift	Benign	0.19	T
Sift4G	Benign	0.24	T
Polyphen		0.0030	B
Vest4		0.14
MutPred		0.47		Loss of sheet (P = 0.1158);
MVP		0.55
MPC		0.43
ClinPred		0.16	T
GERP RS		2.9
Varity_R		0.25
gMVP		0.57

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: rs536332070; hg19: chr7-86468296;