rs1451230055
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_007327.4(GRIN1):c.2479G>A(p.Gly827Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
GRIN1
NM_007327.4 missense
NM_007327.4 missense
Scores
11
7
1
Clinical Significance
Conservation
PhyloP100: 7.43
Genes affected
GRIN1 (HGNC:4584): (glutamate ionotropic receptor NMDA type subunit 1) The protein encoded by this gene is a critical subunit of N-methyl-D-aspartate receptors, members of the glutamate receptor channel superfamily which are heteromeric protein complexes with multiple subunits arranged to form a ligand-gated ion channel. These subunits play a key role in the plasticity of synapses, which is believed to underlie memory and learning. Cell-specific factors are thought to control expression of different isoforms, possibly contributing to the functional diversity of the subunits. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
In a transmembrane_region Helical (size 20) in uniprot entity NMDZ1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_007327.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the GRIN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 75 curated pathogenic missense variants (we use a threshold of 10). The gene has 49 curated benign missense variants. Gene score misZ: 6.2157 (above the threshold of 3.09). Trascript score misZ: 6.6419 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental and epileptic encephalopathy 101, neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, autosomal dominant non-syndromic intellectual disability, complex neurodevelopmental disorder, intellectual disability, autosomal dominant 8.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.985
PP5
Variant 9-137163794-G-A is Pathogenic according to our data. Variant chr9-137163794-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 487503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137163794-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Apr 01, 2017
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Apr 02, 2020
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Published functional studies demonstrate G827R dramatically alters receptor gating (Amin et al., 2018); No data available from ethnically-matched control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 33144682, 30139991, 29365063, 30217972, 25326635, 29124671, 28389307, 27652284, 26633542, 27164704) -
Intellectual disability, autosomal dominant 8 Pathogenic:2
-
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Nov 30, 2022
Institute of Immunology and Genetics Kaiserslautern
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
ACMG Criteria: PS2, PS3, PM1,PM2_P, PP3, PP5; Variant was found in heterozygous state. De novo-status was confirmed via in-house segregation analysis. -
NEURODEVELOPMENTAL DISORDER WITH HYPERKINETIC MOVEMENTS AND WITH OR WITHOUT SEIZURES, AUTOSOMAL DOMINANT Pathogenic:1
Mar 28, 2022
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Neurodevelopmental disorder Pathogenic:1
Oct 06, 2020
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;.;T;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;.;.;.;M;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D
Polyphen
D;D;.;.;.;D;.
Vest4
MutPred
Gain of MoRF binding (P = 0.0139);Gain of MoRF binding (P = 0.0139);.;.;.;Gain of MoRF binding (P = 0.0139);.;
MVP
MPC
3.7
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