NM_000828.5:c.1200T>G

Variant names:

• chrX-123403426-T-G
• NM_000828.5:c.1200T>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000828.5(GRIA3):​c.1200T>G​(p.Asn400Lys) variant causes a missense change involving the alteration of a non-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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: GRIA3 NM_000828.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.14

Genes affected

GRIA3 (HGNC:4573): (glutamate ionotropic receptor AMPA type subunit 3) 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 at this locus results in different isoforms, which may vary in their signal transduction properties. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIA3	NM_000828.5	c.1200T>G	p.Asn400Lys	missense_variant	Exon 9 of 16	ENST00000622768.5	NP_000819.4
GRIA3	NM_007325.5	c.1200T>G	p.Asn400Lys	missense_variant	Exon 9 of 16	ENST00000620443.2	NP_015564.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIA3	ENST00000620443.2	c.1200T>G	p.Asn400Lys	missense_variant	Exon 9 of 16	1	NM_007325.5	ENSP00000478489.1
GRIA3	ENST00000622768.5	c.1200T>G	p.Asn400Lys	missense_variant	Exon 9 of 16	5	NM_000828.5	ENSP00000481554.1
GRIA3	ENST00000620581.4	n.1200T>G		non_coding_transcript_exon_variant	Exon 9 of 17	1		ENSP00000481875.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 400 of the GRIA3 protein (p.Asn400Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GRIA3-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GRIA3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;T;D;.
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D;D;.;D
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Pathogenic	2.9	M;.;M;M
PrimateAI	Uncertain	0.74	T
REVEL	Benign	0.21
Sift4G	Uncertain	0.031	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.79
MutPred		0.52		Gain of ubiquitination at N400 (P = 0.0198);Gain of ubiquitination at N400 (P = 0.0198);Gain of ubiquitination at N400 (P = 0.0198);Gain of ubiquitination at N400 (P = 0.0198);
MVP		1.0
ClinPred		0.94	D
GERP RS		2.2
Varity_R		0.58
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-122537277;