rs1554274719
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5
The NM_001278064.2(GRM1):āc.785A>Gā(p.Tyr262Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
GRM1
NM_001278064.2 missense
NM_001278064.2 missense
Scores
9
4
4
Clinical Significance
Conservation
PhyloP100: 8.89
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, GRM1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.861
PP5
?
Variant 6-146159432-A-G is Pathogenic according to our data. Variant chr6-146159432-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 438856.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GRM1 | NM_001278064.2 | c.785A>G | p.Tyr262Cys | missense_variant | 2/8 | ENST00000282753.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GRM1 | ENST00000282753.6 | c.785A>G | p.Tyr262Cys | missense_variant | 2/8 | 1 | NM_001278064.2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461862Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727232
GnomAD4 exome
AF:
AC:
1
AN:
1461862
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
727232
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Spinocerebellar ataxia 44 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 18, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;M;M
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;D
REVEL
Pathogenic
Sift
Benign
T;T;T;T;T
Sift4G
Benign
T;D;T;D;T
Polyphen
D;D;.;D;D
Vest4
MutPred
Loss of phosphorylation at Y262 (P = 0.0227);Loss of phosphorylation at Y262 (P = 0.0227);Loss of phosphorylation at Y262 (P = 0.0227);Loss of phosphorylation at Y262 (P = 0.0227);Loss of phosphorylation at Y262 (P = 0.0227);
MVP
MPC
1.9
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at