rs2227098

Variant names:

• chrX-123361111-C-T
• rs2227098
• NM_000828.5:c.750+6148C>T

Variant summary

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

The NM_007325.5(GRIA3):​c.750+6148C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.427 in 109,420 control chromosomes in the GnomAD database, including 7,319 homozygotes. There are 13,292 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 0.43 (7319 hom., 13287 hem., cov: 22)
  • Exomes 𝑓: 0.56 (0 hom. 5 hem.)
• Consequence: GRIA3 NM_007325.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.251
• Publications: 3 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007325.5. 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
	GRIA3	NM_000828.5	MANE Plus Clinical	c.750+6148C>T		intron	N/A	NP_000819.4	P42263-1
	GRIA3	NM_007325.5	MANE Select	c.750+6148C>T		intron	N/A	NP_015564.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA3	ENST00000620443.2	TSL:1 MANE Select	c.750+6148C>T		intron	N/A	ENSP00000478489.1	P42263-2
	GRIA3	ENST00000622768.5	TSL:5 MANE Plus Clinical	c.750+6148C>T		intron	N/A	ENSP00000481554.1	P42263-1
	GRIA3	ENST00000620581.4	TSL:1	n.750+6148C>T		intron	N/A	ENSP00000481875.1	A0A087WYJ6

Frequencies

GnomAD3 genomes AF: 0.427 AC: 46687 AN: 109362 Hom.: 7317 Cov.: 22

Gnomad AFR AF: 0.382

Gnomad AMI AF: 0.478

Gnomad AMR AF: 0.421

Gnomad ASJ AF: 0.542

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.349

Gnomad FIN AF: 0.436

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.445

GnomAD4 exome AF: 0.556 AC: 5 AN: 9 Hom.: 0 AF XY: 0.556 AC XY: 5 AN XY: 9

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1

European-Non Finnish (NFE) AF: 0.714 AC: 5 AN: 7

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.427 AC: 46701 AN: 109411 Hom.: 7319 Cov.: 22 AF XY: 0.418 AC XY: 13287 AN XY: 31765

African (AFR) AF: 0.382 AC: 11465 AN: 30039

American (AMR) AF: 0.421 AC: 4315 AN: 10253

Ashkenazi Jewish (ASJ) AF: 0.542 AC: 1422 AN: 2622

East Asian (EAS) AF: 0.386 AC: 1329 AN: 3441

South Asian (SAS) AF: 0.351 AC: 882 AN: 2510

European-Finnish (FIN) AF: 0.436 AC: 2463 AN: 5650

Middle Eastern (MID) AF: 0.597 AC: 129 AN: 216

European-Non Finnish (NFE) AF: 0.451 AC: 23710 AN: 52532

Other (OTH) AF: 0.450 AC: 668 AN: 1483

Alfa AF: 0.445 Hom.: 30874

Bravo AF: 0.432

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.64
DANN	Benign	0.34
PhyloP100		-0.25
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: rs2227098; hg19: chrX-122494962;