rs1555050165

Variant names:

• chr11-105926814-A-G
• rs1555050165
• NM_000829.4:c.1921A>G
• GRIA4 p.Asn641Asp

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM1 PM2 PP3_Strong PP5_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 (★). ClinVar reports functional evidence for this variant: "SCV000741280: 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).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRIA4 NM_000829.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 9.32
• Publications: 1 publications found

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]

GRIA4 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with or without seizures and gait abnormalities

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics, ClinGen, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000741280: 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).
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000829.4
• PM2: Very rare variant in population databases, with high coverage
• 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 VariationId is 446207.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000829.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA4	NM_000829.4	MANE Select	c.1921A>G	p.Asn641Asp	missense	Exon 13 of 17	NP_000820.4	P48058-1
	GRIA4	NM_001440382.1		c.1921A>G	p.Asn641Asp	missense	Exon 13 of 17	NP_001427311.1
	GRIA4	NM_001440383.1		c.1921A>G	p.Asn641Asp	missense	Exon 13 of 17	NP_001427312.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA4	ENST00000282499.10	TSL:5 MANE Select	c.1921A>G	p.Asn641Asp	missense	Exon 13 of 17	ENSP00000282499.5	P48058-1
	GRIA4	ENST00000530497.1	TSL:1	c.1921A>G	p.Asn641Asp	missense	Exon 12 of 16	ENSP00000435775.1	P48058-1
	GRIA4	ENST00000525187.6	TSL:1	c.1921A>G	p.Asn641Asp	missense	Exon 13 of 17	ENSP00000432180.1	G3V164

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)
1	-	-	Intellectual disability (1)
1	-	-	Neurodevelopmental disorder with or without seizures and gait abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		9.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.95
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1555050165;

hg19: chr11-105797540;