rs765556214

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 7P and 2B. PM1PM5PP2PP5_ModerateBP4BS2_Supporting

The NM_000829.4(GRIA4):c.2090G>A(p.Arg697Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000033 in 1,608,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R697P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

GRIA4
NM_000829.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.94

Variant links:

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]

GRIA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a topological_domain Extracellular (size 174) in uniprot entity GRIA4_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_000829.4

PM5

Other missense variant is known to change same aminoacid residue: 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.

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-A is Pathogenic according to our data. Variant chr11-105933765-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2500997.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.1899972). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAd4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIA4	NM_000829.4 linkuse as main transcript	c.2090G>A	p.Arg697Gln	missense_variant	14/17	ENST00000282499.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIA4	ENST00000282499.10 linkuse as main transcript	c.2090G>A	p.Arg697Gln	missense_variant	14/17	5	NM_000829.4	A1	P48058-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248092

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134012

show subpopulations

Gnomad AFR exome

AF:

0.0000623

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000268

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000316

AC:

AN:

1456124

Hom.:

Cov.:

AF XY:

0.0000235

AC XY:

AN XY:

724476

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000406

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neurodevelopmental disorder with or without seizures and gait abnormalities

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Institute of Human Genetics, University of Leipzig Medical Center

May 05, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;.;.;T

Eigen

Benign

-0.099

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.83

T;T;.;.

M_CAP

Benign

0.0084

MetaRNN

Benign

0.19

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.090

N;.;.;N

MutationTaster

Benign

0.90

D;D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.0

N;N;N;N

REVEL

Benign

0.037

Sift

Uncertain

0.010

D;D;D;D

Sift4G

Benign

0.16

T;T;T;T

Polyphen

0.0020

B;B;B;B

Vest4

0.28

MutPred

0.39

Loss of MoRF binding (P = 0.0197);Loss of MoRF binding (P = 0.0197);Loss of MoRF binding (P = 0.0197);Loss of MoRF binding (P = 0.0197);

MVP

0.47

MPC

1.4

ClinPred

0.32

GERP RS

4.3

Varity_R

0.14

gMVP

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over