rs1555050165

Positions:

• chr11-105926814-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 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 (★).

• 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

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]

ACMG classification

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

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

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: dbNSFP v4.3

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;.;.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;.;.
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	3.7	H;.;.;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.94
MutPred		0.92		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		0.89
MPC		2.3
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.95
gMVP		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555050165; hg19: chr11-105797540;