rs1555050165
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate
The NM_000829.4(GRIA4):c.1921A>G(p.Asn641Asp) 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 Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
GRIA4
NM_000829.4 missense
NM_000829.4 missense
Scores
12
5
2
Clinical Significance
Conservation
PhyloP100: 9.32
Genes affected
GRIA4 (HGNC:4574): (glutamate ionotropic receptor AMPA type subunit 4) Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. These receptors are heteromeric protein complexes composed of multiple subunits, arranged to form ligand-gated ion channels. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. The subunit encoded by this gene belongs to a family of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate)-sensitive glutamate receptors, and is subject to RNA editing (AGA->GGA; R->G). Alternative splicing of this gene results in transcript variants encoding different isoforms, which may vary in their signal transduction properties. Some haplotypes of this gene show a positive association with schizophrenia. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000829.4
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, GRIA4
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.977
PP5
?
Variant 11-105926814-A-G is Pathogenic according to our data. Variant chr11-105926814-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446207.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-105926814-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GRIA4 | NM_000829.4 | c.1921A>G | p.Asn641Asp | missense_variant | 13/17 | ENST00000282499.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GRIA4 | ENST00000282499.10 | c.1921A>G | p.Asn641Asp | missense_variant | 13/17 | 5 | NM_000829.4 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 28
GnomAD4 exome
Cov.:
28
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 09, 2024 | The c.1921A>G (p.N641D) alteration is located in exon 13 (coding exon 12) of the GRIA4 gene. This alteration results from an A to G substitution at nucleotide position 1921, causing the asparagine (N) at amino acid position 641 to be replaced by an aspartic acid (D). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported de novo in one individual with features consistent with GRIA4-related neurodevelopmental disorder (Martin, 2017). A de novo GRIN1 c.1950C>G (p.N650K) alteration (orthologous to N641 of GRIA4) was reported in one individual with severe intellectual disability, complex partial seizures, chorea, dyskinesia, spasticity, progressive microcephaly, feeding difficulties, brain MRI abnormalities (thinning of the corpus callosum, ventriculomegaly, and mild cerebellar atrophy), and mildly dysmorphic facial features (Ohba, 2015). This amino acid position is highly conserved in available vertebrate species. The p.N641D amino acid is located in an alpha helix in the transmembrane region known as the M3 segment of GluR4. The M3 segment of each subunit of the tetrameric receptor channel plays a critical role in the high influx of Ca2+ ions through the receptor channel under physiological conditions and contains the most conserved motif common to all glutamate receptor subunits (SYTANLAAF), which is a critical determinant of channel gating in glutamate receptors (Yuan, 2005). In house structural modeling at Ambry Genetics of the c.1921A>G (p.N641D) alteration suggests that the alteration is likely disrupting the gating mechanism of the channel. Mutagenesis studies have demonstrated the striking effect of amino acid substitutions in this segment on glutamate receptor function, especially at the highly conserved asparagine (N) residue within the motif (Jatzke, 2003). Amino acid substitutions of this asparagine (N) in M3 (N641 in GRIA4) were shown to strongly diminish Ca2+ permeability under physiological conditions indicating a significant role for this asparagine during Ca2+ influx in the GluR4 (and other glutamate) receptors (Jatzke, 2003). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. - |
Neurodevelopmental disorder with or without seizures and gait abnormalities Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 07, 2018 | - - |
Intellectual disability Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;.;.
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.;.;H
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
D;D;D;D
Vest4
MutPred
Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP
MPC
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