Variant 6-146434251-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0180

Variant links:

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]

GRM1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. 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=0.06509107).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM1	NM_001278064.2 linkuse as main transcript	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 linkuse as main transcript	c.3040C>A	p.Pro1014Thr	missense_variant	8/8	1	NM_001278064.2	P1	Q13255-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000413

AC:

AN:

242350

Hom.:

AF XY:

0.00000764

AC XY:

AN XY:

130924

show subpopulations

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:

AN:

1447604

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718530

show subpopulations

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.:

ExAC

AF:

0.00000824

AC:

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

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.090

T;T

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.52

T;.

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.065

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.90

L;L

MutationTaster

Benign

1.0

D;D;D;D;N;N

PrimateAI

Benign

0.36

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over