rs761033890

chr6-146434251-C-Achr6-146434251-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_001278064.2(GRM1):c.3040C>A(p.Pro1014Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,604 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. P1014S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GRM1 NM_001278064.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0180

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GRM1
• BP4: Computational evidence support a benign effect (MetaRNN=0.06509107).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM1	NM_001278064.2	c.3040C>A	p.Pro1014Thr	missense_variant	8/8	ENST00000282753.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM1	ENST00000282753.6	c.3040C>A	p.Pro1014Thr	missense_variant	8/8	1	NM_001278064.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000413 AC: 1 AN: 242350 Hom.: 0 AF XY: 0.00000764 AC XY: 1 AN XY: 130924

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000348

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447604 Hom.: 0 Cov.: 37 AF XY: 0.00000139 AC XY: 1 AN XY: 718530

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: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	14
Dann	Benign	0.87
DEOGEN2	Benign	0.090	T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.52	T;.
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.065	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	D;D;D;D;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.51	N;N
REVEL	Benign	0.19
Sift	Benign	0.41	T;T
Sift4G	Benign	0.068	T;T
Polyphen		0.012	B;B
Vest4		0.28
MutPred		0.23		Gain of phosphorylation at P1014 (P = 0.0339);Gain of phosphorylation at P1014 (P = 0.0339);
MVP		0.52
MPC		0.82
ClinPred		0.029	T
GERP RS		0.86
Varity_R		0.071
gMVP		0.49

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: rs761033890; hg19: chr6-146755387;