11-105933765-G-C

Position:

• chr11-105933765-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2 PP2 PP5_Moderate BP4

The NM_000829.4(GRIA4):​c.2090G>C​(p.Arg697Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRIA4 NM_000829.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 3.94

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GRIA4. . Gene score misZ 3.4196 (greater than the threshold 3.09). Trascript score misZ 3.1365 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with or without seizures and gait abnormalities.
• PP5: Variant 11-105933765-G-C is Pathogenic according to our data. Variant chr11-105933765-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446210.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-105933765-G-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.3847937). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIA4	NM_000829.4	c.2090G>C	p.Arg697Pro	missense_variant	14/17	ENST00000282499.10	NP_000820.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIA4	ENST00000282499.10	c.2090G>C	p.Arg697Pro	missense_variant	14/17	5	NM_000829.4	ENSP00000282499	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with or without seizures and gait abnormalities Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 10, 2023	Criteria applied: PS2, PM1, PM2_SUP -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 07, 2018	- -

Intellectual disability Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

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	0.99
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;.;.;D
Eigen	Benign	0.044
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D;.;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.;.;L
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Benign	0.19
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.039	D;D;D;D
Polyphen		0.026	B;B;B;B
Vest4		0.55
MutPred		0.57		Loss of MoRF binding (P = 0.002);Loss of MoRF binding (P = 0.002);Loss of MoRF binding (P = 0.002);Loss of MoRF binding (P = 0.002);
MVP		0.50
MPC		2.1
ClinPred		0.94	D
GERP RS		4.3
Varity_R		0.78
gMVP		0.96

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: rs765556214; hg19: chr11-105804491;