chrX-123184573-G-A

Position:

• chrX-123184573-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000828.5(GRIA3):​c.38G>A​(p.Arg13Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,127 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: GRIA3 NM_000828.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.188

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13389954).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIA3	NM_000828.5	c.38G>A	p.Arg13Gln	missense_variant	1/16	ENST00000622768.5	NP_000819.4
GRIA3	NM_007325.5	c.38G>A	p.Arg13Gln	missense_variant	1/16	ENST00000620443.2	NP_015564.5
GRIA3	NM_001256743.2	c.38G>A	p.Arg13Gln	missense_variant	1/4		NP_001243672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIA3	ENST00000620443.2	c.38G>A	p.Arg13Gln	missense_variant	1/16	1	NM_007325.5	ENSP00000478489	P4
GRIA3	ENST00000622768.5	c.38G>A	p.Arg13Gln	missense_variant	1/16	5	NM_000828.5	ENSP00000481554	A1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097127 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 362511

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 20

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2024

The c.38G>A (p.R13Q) alteration is located in exon 1 (coding exon 1) of the GRIA3 gene. This alteration results from a G to A substitution at nucleotide position 38, causing the arginine (R) at amino acid position 13 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.071	T;T;T;T;T;.
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.73	.;T;T;T;.;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	.;N;.;.;N;N
MutationTaster	Benign	0.99	N;N;N;N;N;N
PrimateAI	Benign	0.28	T
Sift4G	Benign	0.15	T;T;T;T;T;T
Polyphen		0.0	.;B;.;.;B;B
Vest4		0.17
MutPred		0.59		Loss of MoRF binding (P = 0.0093);Loss of MoRF binding (P = 0.0093);Loss of MoRF binding (P = 0.0093);Loss of MoRF binding (P = 0.0093);Loss of MoRF binding (P = 0.0093);Loss of MoRF binding (P = 0.0093);
MVP		0.63
ClinPred		0.089	T
GERP RS		-1.2
Varity_R		0.055
gMVP		0.35

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-122318425;