Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000828.5(GRIA3):c.1888G>A(p.Gly630Arg) 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. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

GRIA3
NM_000828.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 10.0

Publications

3 publications found

Variant links:

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

GRIA3 links:

ENSG00000307341 (HGNC:):

ENSG00000307341 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PS1

Transcript NM_000828.5 (GRIA3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

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, 0.992

PP5

Variant X-123427951-G-A is Pathogenic according to our data. Variant chrX-123427951-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 981267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000828.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA3	NM_000828.5	MANE Plus Clinical	c.1888G>A	p.Gly630Arg	missense	Exon 12 of 16	NP_000819.4
	GRIA3	NM_007325.5	MANE Select	c.1888G>A	p.Gly630Arg	missense	Exon 12 of 16	NP_015564.5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GRIA3	ENST00000620443.2	TSL:1 MANE Select	c.1888G>A	p.Gly630Arg	missense	Exon 12 of 16	ENSP00000478489.1
GRIA3	ENST00000622768.5	TSL:5 MANE Plus Clinical	c.1888G>A	p.Gly630Arg	missense	Exon 12 of 16	ENSP00000481554.1
GRIA3	ENST00000620581.4	TSL:1	n.1888G>A		non_coding_transcript_exon	Exon 12 of 17	ENSP00000481875.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1083394

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

350504

African (AFR)

AF:

0.00

AC:

AN:

26114

American (AMR)

AF:

0.00

AC:

AN:

35170

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19281

East Asian (EAS)

AF:

0.00

AC:

AN:

30155

South Asian (SAS)

AF:

0.00

AC:

AN:

53803

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40494

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4047

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

828718

Other (OTH)

AF:

0.00

AC:

AN:

45612

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability (1)

not provided (1)

Seizure (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

PhyloP100

PrimateAI

Pathogenic

0.95

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.96

MutPred

0.93

Gain of MoRF binding (P = 0.0182)

MVP

1.0

ClinPred

1.0

GERP RS

5.4

Varity_R

0.99

gMVP

1.0

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs587777361

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over