rs590928

Variant names:

• chr11-105715845-G-A
• rs590928
• NM_000829.4:c.248-37136G>A

Variant summary

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

The NM_000829.4(GRIA4):​c.248-37136G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 151,856 control chromosomes in the GnomAD database, including 22,374 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 (22374 hom., cov: 31)
• Consequence: GRIA4 NM_000829.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.855
• 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.603 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.248-37136G>A		intron	N/A	NP_000820.4	P48058-1
	GRIA4	NM_001440382.1		c.248-37136G>A		intron	N/A	NP_001427311.1
	GRIA4	NM_001440383.1		c.248-37136G>A		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.248-37136G>A		intron	N/A	ENSP00000282499.5	P48058-1
	GRIA4	ENST00000530497.1	TSL:1	c.248-37136G>A		intron	N/A	ENSP00000435775.1	P48058-1
	GRIA4	ENST00000525187.6	TSL:1	c.248-37136G>A		intron	N/A	ENSP00000432180.1	G3V164

Frequencies

GnomAD3 genomes AF: 0.542 AC: 82171 AN: 151742 Hom.: 22358 Cov.: 31

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.447

Gnomad AMR AF: 0.613

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.473

Gnomad FIN AF: 0.605

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.540

Gnomad OTH AF: 0.525

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

GnomAD4 genome AF: 0.541 AC: 82229 AN: 151856 Hom.: 22374 Cov.: 31 AF XY: 0.546 AC XY: 40505 AN XY: 74204

African (AFR) AF: 0.525 AC: 21730 AN: 41414

American (AMR) AF: 0.613 AC: 9349 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 1913 AN: 3466

East Asian (EAS) AF: 0.424 AC: 2168 AN: 5110

South Asian (SAS) AF: 0.475 AC: 2283 AN: 4810

European-Finnish (FIN) AF: 0.605 AC: 6397 AN: 10566

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.540 AC: 36713 AN: 67930

Other (OTH) AF: 0.523 AC: 1102 AN: 2106

Alfa AF: 0.537 Hom.: 11290

Bravo AF: 0.548

Asia WGS AF: 0.480 AC: 1670 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.31
DANN	Benign	0.70
PhyloP100		-0.85
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs590928; hg19: chr11-105586571;