rs79336287

Positions:

• chr6-146434417-C-A
• chr6-146434417-C-G
• chr6-146434417-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000282753.6(GRM1):​c.3206C>A​(p.Pro1069Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. P1069L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: GRM1 ENST00000282753.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.28

Genes affected

GRM1 (HGNC:4593): (glutamate metabotropic receptor 1) This gene encodes a metabotropic glutamate receptor that functions by activating phospholipase C. 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 canonical alpha isoform of the encoded protein is a disulfide-linked homodimer whose activity is mediated by a G-protein-coupled phosphatidylinositol-calcium second messenger system. This gene may be associated with many disease states, including schizophrenia, bipolar disorder, depression, and breast cancer. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GRM1. . Gene score misZ 2.5817 (greater than the threshold 3.09). Trascript score misZ 3.6372 (greater than threshold 3.09). GenCC has associacion of gene with spinocerebellar ataxia 44, autosomal recessive spinocerebellar ataxia 13.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13485444).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM1	NM_001278064.2	c.3206C>A	p.Pro1069Gln	missense_variant	8/8	ENST00000282753.6	NP_001264993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRM1	ENST00000282753.6	c.3206C>A	p.Pro1069Gln	missense_variant	8/8	1	NM_001278064.2	ENSP00000282753	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 59

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.072	T;T
Eigen	Benign	0.059
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.58	T;.
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	1.0	D;D;D;D;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.020	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.27	T;T
Sift4G	Benign	0.71	T;T
Polyphen		0.17	B;B
Vest4		0.27
MutPred		0.34		Loss of glycosylation at P1069 (P = 5e-04);Loss of glycosylation at P1069 (P = 5e-04);
MVP		0.39
MPC		0.64
ClinPred		0.40	T
GERP RS		4.8
Varity_R		0.10
gMVP		0.53

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: rs79336287; hg19: chr6-146755553;