NM_000829.4:c.2294+3077T>G

Variant names:

• chr11-105937046-T-G
• rs589104
• NM_000829.4:c.2294+3077T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000829.4(GRIA4):​c.2294+3077T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.543 in 151,898 control chromosomes in the GnomAD database, including 22,421 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.54 (22421 hom., cov: 32)
• Consequence: GRIA4 NM_000829.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21
• Publications: 3 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: G2P, ClinGen, Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.597 is higher than 0.05.

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.2294+3077T>G		intron	N/A	NP_000820.4	P48058-1
	GRIA4	NM_001440382.1		c.2294+3077T>G		intron	N/A	NP_001427311.1
	GRIA4	NM_001440383.1		c.2294+3077T>G		intron	N/A	NP_001427312.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA4	ENST00000282499.10	TSL:5 MANE Select	c.2294+3077T>G		intron	N/A	ENSP00000282499.5	P48058-1
	GRIA4	ENST00000530497.1	TSL:1	c.2294+3077T>G		intron	N/A	ENSP00000435775.1	P48058-1
	GRIA4	ENST00000525187.6	TSL:1	c.2294+3077T>G		intron	N/A	ENSP00000432180.1	G3V164

Frequencies

GnomAD3 genomes AF: 0.543 AC: 82414 AN: 151780 Hom.: 22418 Cov.: 32

Gnomad AFR AF: 0.564

Gnomad AMI AF: 0.535

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.614

Gnomad SAS AF: 0.615

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.534

Gnomad OTH AF: 0.537

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.543 AC: 82448 AN: 151898 Hom.: 22421 Cov.: 32 AF XY: 0.542 AC XY: 40200 AN XY: 74234

African (AFR) AF: 0.564 AC: 23351 AN: 41414

American (AMR) AF: 0.505 AC: 7703 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1955 AN: 3462

East Asian (EAS) AF: 0.613 AC: 3158 AN: 5154

South Asian (SAS) AF: 0.615 AC: 2963 AN: 4814

European-Finnish (FIN) AF: 0.500 AC: 5278 AN: 10562

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.534 AC: 36254 AN: 67922

Other (OTH) AF: 0.535 AC: 1126 AN: 2106

Alfa AF: 0.540 Hom.: 10699

Bravo AF: 0.546

Asia WGS AF: 0.598 AC: 2079 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.085
DANN	Benign	0.44
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs589104; hg19: chr11-105807772;