chrX-123427954-C-A

Variant names:

• chrX-123427954-C-A
• rs137852351
• NM_000828.5:c.1891C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_000828.5(GRIA3):​c.1891C>A​(p.Arg631Ser) variant causes a missense change involving the alteration of a non-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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R631C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: GRIA3 NM_000828.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.80
• Publications: 6 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: Likely_pathogenic. The variant received 8 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, 0.993
• PP5: Variant X-123427954-C-A is Pathogenic according to our data. Variant chrX-123427954-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10357.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIA3	NM_000828.5	c.1891C>A	p.Arg631Ser	missense_variant	Exon 12 of 16	ENST00000622768.5	NP_000819.4
GRIA3	NM_007325.5	c.1891C>A	p.Arg631Ser	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.1891C>A	p.Arg631Ser	missense_variant	Exon 12 of 16	1	NM_007325.5	ENSP00000478489.1
GRIA3	ENST00000622768.5	c.1891C>A	p.Arg631Ser	missense_variant	Exon 12 of 16	5	NM_000828.5	ENSP00000481554.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Syndromic X-linked intellectual disability 94 Pathogenic:1

Nov 13, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;D;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D;D;.;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	4.3	H;.;H;H
PhyloP100		1.8
PrimateAI	Pathogenic	0.90	D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.99
MutPred		0.97		Gain of glycosylation at R631 (P = 0.013);Gain of glycosylation at R631 (P = 0.013);Gain of glycosylation at R631 (P = 0.013);Gain of glycosylation at R631 (P = 0.013);
MVP		1.0
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.99
gMVP		1.0
Mutation Taster		=2/98	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: rs137852351; hg19: chrX-122561805;