rs1057521721

Variant names:

• chrX-123428020-G-A
• rs1057521721
• NM_000828.5:c.1957G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-123428020-G-A
• chrX-123428020-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_007325.5(GRIA3):​c.1957G>A​(p.Ala653Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: GRIA3 NM_007325.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 10.0

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_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant X-123428020-G-A is Pathogenic according to our data. Variant chrX-123428020-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 383739.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=3}. Variant chrX-123428020-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIA3	NM_000828.5	c.1957G>A	p.Ala653Thr	missense_variant	Exon 12 of 16	ENST00000622768.5	NP_000819.4
GRIA3	NM_007325.5	c.1957G>A	p.Ala653Thr	missense_variant	Exon 12 of 16	ENST00000620443.2	NP_015564.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIA3	ENST00000620443.2	c.1957G>A	p.Ala653Thr	missense_variant	Exon 12 of 16	1	NM_007325.5	ENSP00000478489.1
GRIA3	ENST00000622768.5	c.1957G>A	p.Ala653Thr	missense_variant	Exon 12 of 16	5	NM_000828.5	ENSP00000481554.1
GRIA3	ENST00000620581.4	n.1957G>A		non_coding_transcript_exon_variant	Exon 12 of 17	1		ENSP00000481875.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Syndromic X-linked intellectual disability 94 Pathogenic:2 Uncertain:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2+PS4_Supporting -

Sep 23, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Wu type X-linked syndromic intellectual developmental disorder (MIM#300699). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32977175). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative change (p.(Ala653Ser)) has been reported once as de novo in an individual with epilepsy and intellectual disability (PMID: 37921875). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported several times as likely pathogenic or pathogenic, and observed in two hemizygous brothers with features including global developmental delay and gross motor delay (PMID: 29016847, ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been shown to have significantly increased agonist potency but no current response (PMID: 37921875). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (Broad Institute, RDNow project). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Oct 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 653 of the GRIA3 protein (p.Ala653Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of GRIA3-related conditions (PMID: 29016847; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 383739). 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. Experimental studies have shown that this missense change affects GRIA3 function (PMID: 29016847). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Apr 14, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect on channel function (Davies et al., 2017); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29016847, 32977175) -

Inborn genetic diseases Pathogenic:1

Oct 03, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A653T pathogenic mutation (also known as c.1957G>A), located in coding exon 12 of the GRIA3 gene, results from a G to A substitution at nucleotide position 1957. The alanine at codon 653 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis.This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant has been determined to be the result of a de novo mutation or has been observed hemizygous in multiple individuals with features consistent with GRIA3-related neurodevelopmental disorder (Davies B et al. Hum Mol Genet, 2017 Oct;26:3869-388; external communication). In multiple assays testing GRIA3 function, this variant showed functionally abnormal results (Davies B et al. Hum Mol Genet, 2017 Oct;26:3869-3882; Rinaldi B et al. Brain, 2024 May;147:1837-1855). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Disrupted sleep-wake cycle with developmental delay and learning difficulty Pathogenic:1

May 25, 2017

Barrett Group, Wellcome Trust Sanger Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;in vitro;in vivo

This was the most likely causal variant identified in this family quartet. GRIA3 encodes GluA3, a subunit of AMPA-type ionotropic glutamate receptors, and has been previously implicated in intellectual disability. The mutation (Ala653Thr) falls within the highly conserved transmembrane domain of the ion channel gate. In vitro, the GRIA3(A653T) mutation stabilizes the channel in the closed conformation. We introduced the orthologous mutation into a mouse strain with CRISPR and found that hemizygous mutants displayed significant differences in the structure of their activity and sleep compared to wild-type littermates. These mutant mice showed significantly fewer brief bouts of activity and sleep than the wild-types. Furthermore, they showed enhanced period lengthening under constant light compared to wild-type mice, suggesting an increased sensitivity to light. Our results suggest a role for GluA3 channel activity in regulation of sleep behavior in both mice and humans. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.80	D;T;D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;.;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.6	L;.;L;L
PrimateAI	Pathogenic	0.87	D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.77
MutPred		0.85		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.99
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.93
gMVP		0.96

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: rs1057521721; hg19: chrX-122561871;