X-123326044-C-G

Position:

• chrX-123326044-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_007325.5(GRIA3):​c.527C>G​(p.Ala176Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,093,464 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: GRIA3 NM_007325.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:1
• Conservation: PhyloP100: 7.54

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIA3	NM_000828.5	c.527C>G	p.Ala176Gly	missense_variant	4/16	ENST00000622768.5	NP_000819.4
GRIA3	NM_007325.5	c.527C>G	p.Ala176Gly	missense_variant	4/16	ENST00000620443.2	NP_015564.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIA3	ENST00000620443.2	c.527C>G	p.Ala176Gly	missense_variant	4/16	1	NM_007325.5	ENSP00000478489.1
GRIA3	ENST00000622768.5	c.527C>G	p.Ala176Gly	missense_variant	4/16	5	NM_000828.5	ENSP00000481554.1
GRIA3	ENST00000620581.4	n.527C>G		non_coding_transcript_exon_variant	4/17	1		ENSP00000481875.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1093464 Hom.: 0 Cov.: 29 AF XY: 0.00000278 AC XY: 1 AN XY: 359108

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: 0.00000239

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

The c.527C>G (p.A176G) alteration is located in exon 4 (coding exon 4) of the GRIA3 gene. This alteration results from a C to G substitution at nucleotide position 527, causing the alanine (A) at amino acid position 176 to be replaced by a glycine (G). 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	0.23
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;T;T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;.;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	0.041	D
MutationAssessor	Benign	1.1	L;.;L;L
PrimateAI	Pathogenic	0.87	D
REVEL	Uncertain	0.60
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.36	B;.;B;B
Vest4		0.67
MutPred		0.56		Loss of catalytic residue at M178 (P = 0.0476);Loss of catalytic residue at M178 (P = 0.0476);Loss of catalytic residue at M178 (P = 0.0476);Loss of catalytic residue at M178 (P = 0.0476);
MVP		0.97
ClinPred		0.94	D
GERP RS		5.7
Varity_R		0.54
gMVP		0.55

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

LitVar

Other links and lift over

dbSNP: rs764670975; hg19: chrX-122459895;