chrX-123452561-G-A

Variant names:

• chrX-123452561-G-A
• rs5911623
• NM_000828.5:c.2077-12304G>A

Variant summary

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

The NM_000828.5(GRIA3):​c.2077-12304G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 110,670 control chromosomes in the GnomAD database, including 3,176 homozygotes. There are 8,428 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 0.26 (3176 hom., 8428 hem., cov: 23)
• Consequence: GRIA3 NM_000828.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.688
• Publications: 1 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIA3	NM_000828.5	c.2077-12304G>A		intron_variant	Intron 12 of 15	ENST00000622768.5	NP_000819.4
GRIA3	NM_007325.5	c.2077-12304G>A		intron_variant	Intron 12 of 15	ENST00000620443.2	NP_015564.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIA3	ENST00000620443.2	c.2077-12304G>A		intron_variant	Intron 12 of 15	1	NM_007325.5	ENSP00000478489.1
GRIA3	ENST00000622768.5	c.2077-12304G>A		intron_variant	Intron 12 of 15	5	NM_000828.5	ENSP00000481554.1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 28473 AN: 110617 Hom.: 3179 Cov.: 23

Gnomad AFR AF: 0.0736

Gnomad AMI AF: 0.366

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.340

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.338

Gnomad OTH AF: 0.253

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

GnomAD4 genome AF: 0.257 AC: 28458 AN: 110670 Hom.: 3176 Cov.: 23 AF XY: 0.255 AC XY: 8428 AN XY: 32992

African (AFR) AF: 0.0733 AC: 2246 AN: 30627

American (AMR) AF: 0.275 AC: 2869 AN: 10438

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 916 AN: 2634

East Asian (EAS) AF: 0.339 AC: 1182 AN: 3482

South Asian (SAS) AF: 0.270 AC: 695 AN: 2574

European-Finnish (FIN) AF: 0.352 AC: 2035 AN: 5785

Middle Eastern (MID) AF: 0.373 AC: 79 AN: 212

European-Non Finnish (NFE) AF: 0.338 AC: 17814 AN: 52742

Other (OTH) AF: 0.250 AC: 376 AN: 1503

Alfa AF: 0.302 Hom.: 24155

Bravo AF: 0.248

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.1
DANN	Benign	0.52
PhyloP100		0.69
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: rs5911623; hg19: chrX-122586412;