rs764670975

Variant names:

• chrX-123326044-C-A
• rs764670975
• NM_000828.5:c.527C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-123326044-C-A
• chrX-123326044-C-G
• chrX-123326044-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_000828.5(GRIA3):​c.527C>A​(p.Ala176Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,093,461 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A176V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: GRIA3 NM_000828.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.54
• 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: 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked complex neurodevelopmental disorder, syndromic X-linked intellectual disability 94, X-linked intellectual disability due to GRIA3 anomalies.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIA3	NM_000828.5	c.527C>A	p.Ala176Glu	missense_variant	Exon 4 of 16	ENST00000622768.5	NP_000819.4
GRIA3	NM_007325.5	c.527C>A	p.Ala176Glu	missense_variant	Exon 4 of 16	ENST00000620443.2	NP_015564.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIA3	ENST00000620443.2	c.527C>A	p.Ala176Glu	missense_variant	Exon 4 of 16	1	NM_007325.5	ENSP00000478489.1
GRIA3	ENST00000622768.5	c.527C>A	p.Ala176Glu	missense_variant	Exon 4 of 16	5	NM_000828.5	ENSP00000481554.1
GRIA3	ENST00000620581.4	n.527C>A		non_coding_transcript_exon_variant	Exon 4 of 17	1		ENSP00000481875.1
ENSG00000307341	ENST00000825206.1	n.562-12094G>T		intron_variant	Intron 5 of 6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1093461 Hom.: 0 Cov.: 29 AF XY: 0.00000278 AC XY: 1 AN XY: 359105

African (AFR) AF: 0.00 AC: 0 AN: 26316

American (AMR) AF: 0.00 AC: 0 AN: 35198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19354

East Asian (EAS) AF: 0.00 AC: 0 AN: 30184

South Asian (SAS) AF: 0.00 AC: 0 AN: 54037

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4121

European-Non Finnish (NFE) AF: 0.00000239 AC: 2 AN: 837783

Other (OTH) AF: 0.00 AC: 0 AN: 45936

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

May 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GRIA3 protein function. ClinVar contains an entry for this variant (Variation ID: 1304437). This variant has not been reported in the literature in individuals affected with GRIA3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 176 of the GRIA3 protein (p.Ala176Glu). -

Dec 19, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.13	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	0.89	D;D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.060	N;.;N;N
PhyloP100		7.5
PrimateAI	Pathogenic	0.90	D
REVEL	Uncertain	0.58
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.91	P;.;P;P
Vest4		0.88
MutPred		0.62		Loss of catalytic residue at M178 (P = 0.0408);Loss of catalytic residue at M178 (P = 0.0408);Loss of catalytic residue at M178 (P = 0.0408);Loss of catalytic residue at M178 (P = 0.0408);
MVP		0.99
ClinPred		0.92	D
GERP RS		5.7
Varity_R		0.54
gMVP		0.87
Mutation Taster		=13/87	disease causing

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: rs764670975; hg19: chrX-122459895;