rs137852352

chrX-123464905-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000828.5(GRIA3):c.2117T>C(p.Met706Thr) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M706L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GRIA3 NM_000828.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.01

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a topological_domain Extracellular (size 174) in uniprot entity GRIA3_HUMAN there are 16 pathogenic changes around while only 0 benign (100%) in NM_000828.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant X-123464905-T-C is Pathogenic according to our data. Variant chrX-123464905-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 10358.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-123464905-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIA3	NM_000828.5	c.2117T>C	p.Met706Thr	missense_variant	13/16	ENST00000622768.5
GRIA3	NM_007325.5	c.2117T>C	p.Met706Thr	missense_variant	13/16	ENST00000620443.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIA3	ENST00000620443.2	c.2117T>C	p.Met706Thr	missense_variant	13/16	1	NM_007325.5	P4
GRIA3	ENST00000622768.5	c.2117T>C	p.Met706Thr	missense_variant	13/16	5	NM_000828.5	A1
GRIA3	ENST00000620581.4	c.2117T>C	p.Met706Thr	missense_variant, NMD_transcript_variant	13/17	1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

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

Nov 13, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;T;D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;.;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	-0.0019	T
MutationAssessor	Pathogenic	3.8	H;.;H;H
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.94	D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.93	P;.;P;P
Vest4		0.89
MutPred		0.93		Loss of catalytic residue at M706 (P = 0.0054);Loss of catalytic residue at M706 (P = 0.0054);Loss of catalytic residue at M706 (P = 0.0054);Loss of catalytic residue at M706 (P = 0.0054);
MVP		1.0
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.97
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: rs137852352; hg19: chrX-122598756;