7-86839013-C-T

Position:

• chr7-86839013-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000840.3(GRM3):​c.1499C>T​(p.Ser500Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRM3 NM_000840.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.15

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33010024).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM3	NM_000840.3	c.1499C>T	p.Ser500Phe	missense_variant	4/6	ENST00000361669.7	NP_000831.2
GRM3	XM_047420268.1	c.1499C>T	p.Ser500Phe	missense_variant	5/7		XP_047276224.1
GRM3	NM_001363522.2	c.1325-11357C>T		intron_variant			NP_001350451.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRM3	ENST00000361669.7	c.1499C>T	p.Ser500Phe	missense_variant	4/6	1	NM_000840.3	ENSP00000355316.2
GRM3	ENST00000439827.1	c.1325-11357C>T		intron_variant		1		ENSP00000398767.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Jun 24, 2022

The c.1499C>T (p.S500F) alteration is located in exon 4 (coding exon 3) of the GRM3 gene. This alteration results from a C to T substitution at nucleotide position 1499, causing the serine (S) at amino acid position 500 to be replaced by a phenylalanine (F). 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	0.19
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	0.81	L
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.047	D
Polyphen		0.17	B
Vest4		0.095
MutPred		0.36		Loss of disorder (P = 0.0024);
MVP		0.56
MPC		0.44
ClinPred		0.84	D
GERP RS		5.9
Varity_R		0.64
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-86468329;