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 Pathogenic. The variant received 12 ACMG points: 12P and 0B. 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). 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 12 ACMG points.

• 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;