chr9-137156676-G-C
Position:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP2PP5_Very_Strong
The NM_007327.4(GRIN1):c.679G>C(p.Asp227His) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,448,130 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D227N) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
GRIN1
NM_007327.4 missense
NM_007327.4 missense
Scores
6
11
2
Clinical Significance
Conservation
PhyloP100: 6.22
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 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, GRIN1
PP5
Variant 9-137156676-G-C is Pathogenic according to our data. Variant chr9-137156676-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137156676-G-C is described in Lovd as [Likely_pathogenic]. Variant chr9-137156676-G-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GRIN1 | NM_007327.4 | c.679G>C | p.Asp227His | missense_variant | 5/20 | ENST00000371561.8 | |
LOC105376328 | XR_007061876.1 | n.3253C>G | non_coding_transcript_exon_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GRIN1 | ENST00000371561.8 | c.679G>C | p.Asp227His | missense_variant | 5/20 | 1 | NM_007327.4 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 genomes
Cov.:
34
GnomAD4 exome AF: 6.91e-7 AC: 1AN: 1448130Hom.: 0 Cov.: 34 AF XY: 0.00000139 AC XY: 1AN XY: 719300
GnomAD4 exome
AF:
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1
AN:
1448130
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Cov.:
34
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AC XY:
1
AN XY:
719300
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 34
GnomAD4 genome
Cov.:
34
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Intellectual disability, autosomal dominant 8;C4693325:Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | Apr 05, 2016 | - - |
NEURODEVELOPMENTAL DISORDER WITH HYPERKINETIC MOVEMENTS WITH OR WITHOUT SEIZURES, AUTOSOMAL RECESSIVE Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 28, 2022 | - - |
Intellectual disability, autosomal dominant 8 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Sep 09, 2015 | This study shows that diverse genetic causes underlie CVI. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;T;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;.;.;.;L;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
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
Loss of phosphorylation at T230 (P = 0.1275);Loss of phosphorylation at T230 (P = 0.1275);.;.;.;Loss of phosphorylation at T230 (P = 0.1275);.;
MVP
MPC
2.6
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