chrX-123184590-G-A

Position:

• chrX-123184590-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000828.5(GRIA3):​c.55G>A​(p.Val19Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000729 in 1,096,843 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 10/17 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: 0.0000073 (0 hom. 6 hem.)
• Consequence: GRIA3 NM_000828.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16498467).
• BS2: High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIA3	NM_000828.5	c.55G>A	p.Val19Ile	missense_variant	1/16	ENST00000622768.5	NP_000819.4
GRIA3	NM_007325.5	c.55G>A	p.Val19Ile	missense_variant	1/16	ENST00000620443.2	NP_015564.5
GRIA3	NM_001256743.2	c.55G>A	p.Val19Ile	missense_variant	1/4		NP_001243672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIA3	ENST00000620443.2	c.55G>A	p.Val19Ile	missense_variant	1/16	1	NM_007325.5	ENSP00000478489	P4
GRIA3	ENST00000622768.5	c.55G>A	p.Val19Ile	missense_variant	1/16	5	NM_000828.5	ENSP00000481554	A1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 183445 Hom.: 0 AF XY: 0.0000147 AC XY: 1 AN XY: 67879

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000244

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000729 AC: 8 AN: 1096843 Hom.: 0 Cov.: 29 AF XY: 0.0000166 AC XY: 6 AN XY: 362223

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: 0.00000951

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 20

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 13, 2022

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with GRIA3-related conditions. This variant is present in population databases (rs747644263, gnomAD 0.002%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 19 of the GRIA3 protein (p.Val19Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.053	T;T;T;T;T;.
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.75	.;T;T;T;.;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.16	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.55	.;N;.;.;N;N
MutationTaster	Benign	0.97	N;N;N;N;N;N
PrimateAI	Uncertain	0.49	T
Sift4G	Benign	0.38	T;T;T;T;T;T
Polyphen		0.0080, 0.013	.;B;.;.;B;B
Vest4		0.29
MutPred		0.36		Loss of catalytic residue at V19 (P = 0.0291);Loss of catalytic residue at V19 (P = 0.0291);Loss of catalytic residue at V19 (P = 0.0291);Loss of catalytic residue at V19 (P = 0.0291);Loss of catalytic residue at V19 (P = 0.0291);Loss of catalytic residue at V19 (P = 0.0291);
MVP		0.50
ClinPred		0.84	D
GERP RS		5.8
Varity_R		0.12
gMVP		0.41

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: rs747644263; hg19: chrX-122318442;