rs1555050171

chr11-105926821-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_000829.4(GRIA4):c.1928C>G(p.Ala643Gly) 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 Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A643D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRIA4 NM_000829.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.91

Genes affected

GRIA4 (HGNC:4574): (glutamate ionotropic receptor AMPA type subunit 4) 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 of this gene results in transcript variants encoding different isoforms, which may vary in their signal transduction properties. Some haplotypes of this gene show a positive association with schizophrenia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000829.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-105926821-C-A is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant where missense usually causes diseases, GRIA4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• PP5: Variant 11-105926821-C-G is Pathogenic according to our data. Variant chr11-105926821-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-105926821-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIA4	NM_000829.4	c.1928C>G	p.Ala643Gly	missense_variant	13/17	ENST00000282499.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIA4	ENST00000282499.10	c.1928C>G	p.Ala643Gly	missense_variant	13/17	5	NM_000829.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Neurodevelopmental disorder with or without seizures and gait abnormalities Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 07, 2018

- -

Intellectual disability Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;.;.
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	3.7	H;.;.;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.72
MutPred		0.90		Loss of stability (P = 0.0915);Loss of stability (P = 0.0915);Loss of stability (P = 0.0915);Loss of stability (P = 0.0915);
MVP		0.84
MPC		2.2
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.94
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1555050171; hg19: chr11-105797547;