X-123427951-G-C

Position:

• chrX-123427951-G-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1_Very_Strong PM2 PP3_Strong PP5

The NM_000828.5(GRIA3):​c.1888G>C​(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. 10/17 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 22)
• Consequence: GRIA3 NM_000828.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P: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 Pathogenic. Variant got 15 ACMG points.

• PS1: Transcript NM_000828.5 (GRIA3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 981267
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-123427951-G-C is Pathogenic according to our data. Variant chrX-123427951-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 127195.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-123427951-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIA3	NM_000828.5	c.1888G>C	p.Gly630Arg	missense_variant	12/16	ENST00000622768.5
GRIA3	NM_007325.5	c.1888G>C	p.Gly630Arg	missense_variant	12/16	ENST00000620443.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIA3	ENST00000620443.2	c.1888G>C	p.Gly630Arg	missense_variant	12/16	1	NM_007325.5	P4
GRIA3	ENST00000622768.5	c.1888G>C	p.Gly630Arg	missense_variant	12/16	5	NM_000828.5	A1
GRIA3	ENST00000620581.4	c.1888G>C	p.Gly630Arg	missense_variant, NMD_transcript_variant	12/17	1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Syndromic X-linked intellectual disability 94 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 11, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;T;D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;.;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.95	D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.96
MutPred		0.93		Gain of MoRF binding (P = 0.0182);Gain of MoRF binding (P = 0.0182);Gain of MoRF binding (P = 0.0182);Gain of MoRF binding (P = 0.0182);
MVP		1.0
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.99
gMVP		1.0

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: rs587777361; hg19: chrX-122561802;