rs12836469

Variant names:

• chrX-123425130-T-C
• rs12836469
• NM_000828.5:c.1878-2811T>C

Variant summary

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

The NM_000828.5(GRIA3):​c.1878-2811T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 110,930 control chromosomes in the GnomAD database, including 3,285 homozygotes. There are 8,685 hemizygotes in GnomAD. 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 0.27 (3285 hom., 8685 hem., cov: 23)
• Consequence: GRIA3 NM_000828.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.395
• Publications: 0 publications found

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]

GRIA3 Gene-Disease associations (from GenCC):

• syndromic X-linked intellectual disability 94

  Inheritance: XL Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• X-linked intellectual disability due to GRIA3 anomalies

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000307341 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIA3	NM_000828.5	c.1878-2811T>C		intron_variant	Intron 11 of 15	ENST00000622768.5	NP_000819.4
GRIA3	NM_007325.5	c.1878-2811T>C		intron_variant	Intron 11 of 15	ENST00000620443.2	NP_015564.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIA3	ENST00000620443.2	c.1878-2811T>C		intron_variant	Intron 11 of 15	1	NM_007325.5	ENSP00000478489.1
GRIA3	ENST00000622768.5	c.1878-2811T>C		intron_variant	Intron 11 of 15	5	NM_000828.5	ENSP00000481554.1

Frequencies

GnomAD3 genomes AF: 0.273 AC: 30276 AN: 110877 Hom.: 3289 Cov.: 23

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.438

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.252

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.296

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

GnomAD4 genome AF: 0.273 AC: 30275 AN: 110930 Hom.: 3285 Cov.: 23 AF XY: 0.262 AC XY: 8685 AN XY: 33182

African (AFR) AF: 0.142 AC: 4363 AN: 30704

American (AMR) AF: 0.343 AC: 3570 AN: 10420

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 871 AN: 2636

East Asian (EAS) AF: 0.186 AC: 656 AN: 3521

South Asian (SAS) AF: 0.436 AC: 1143 AN: 2621

European-Finnish (FIN) AF: 0.232 AC: 1374 AN: 5926

Middle Eastern (MID) AF: 0.255 AC: 54 AN: 212

European-Non Finnish (NFE) AF: 0.334 AC: 17626 AN: 52700

Other (OTH) AF: 0.291 AC: 442 AN: 1521

Alfa AF: 0.322 Hom.: 19150

Bravo AF: 0.273

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.93
DANN	Benign	0.74
PhyloP100		0.40
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: rs12836469; hg19: chrX-122558981;