chrX-123428020-G-A

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM1 PM2 PM5 PP2 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). ClinVar reports functional evidence for this variant: "SCV000524224: Published functional studies demonstrate a damaging effect on channel function (Davies et al., 2017)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A653S) has been classified as Pathogenic.

• 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
• Publications: 5 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000524224: Published functional studies demonstrate a damaging effect on channel function (Davies et al., 2017); SCV003445771: Experimental studies have shown that this missense change affects GRIA3 function (PMID: 29016847).; SCV000579326: 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.; SCV005086582: "This variant has been shown to have significantly increased agonist potency but no current response (PMID: 37921875)."; SCV000850755: 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).
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_007325.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-123428020-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2500994.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.951
• 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 VariationId is 383739.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007325.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA3	NM_000828.5	MANE Plus Clinical	c.1957G>A	p.Ala653Thr	missense	Exon 12 of 16	NP_000819.4	P42263-1
	GRIA3	NM_007325.5	MANE Select	c.1957G>A	p.Ala653Thr	missense	Exon 12 of 16	NP_015564.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA3	ENST00000620443.2	TSL:1 MANE Select	c.1957G>A	p.Ala653Thr	missense	Exon 12 of 16	ENSP00000478489.1	P42263-2
	GRIA3	ENST00000622768.5	TSL:5 MANE Plus Clinical	c.1957G>A	p.Ala653Thr	missense	Exon 12 of 16	ENSP00000481554.1	P42263-1
	GRIA3	ENST00000620581.4	TSL:1	n.1957G>A		non_coding_transcript_exon	Exon 12 of 17	ENSP00000481875.1	A0A087WYJ6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	Syndromic X-linked intellectual disability 94 (3)
2	-	-	not provided (2)
1	-	-	Disrupted sleep-wake cycle with developmental delay and learning difficulty (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.6	L
PhyloP100		10
PrimateAI	Pathogenic	0.87	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.85		Gain of sheet (P = 0.0477)
MVP		0.99
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.93
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs1057521721; hg19: chrX-122561871;