Variant chr11-105753074-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3PP5_Moderate

The NM_000829.4(GRIA4):c.341A>G(p.His114Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GRIA4
NM_000829.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.32

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.827

PP5

Variant 11-105753074-A-G is Pathogenic according to our data. Variant chr11-105753074-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1708322.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIA4	NM_000829.4 linkuse as main transcript	c.341A>G	p.His114Arg	missense_variant	4/17	ENST00000282499.10	NP_000820.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIA4	ENST00000282499.10 linkuse as main transcript	c.341A>G	p.His114Arg	missense_variant	4/17	5	NM_000829.4	ENSP00000282499	A1	P48058-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461642

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

See cases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 10, 2021

ACMG categories: PS2,PM1,PM2,BP1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

.;D;.;.;T;.;D

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

.;D;D;D;D;.;.

M_CAP

Benign

0.054

MetaRNN

Pathogenic

0.83

D;D;D;D;D;D;D

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.2

M;M;.;M;.;.;M

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-5.5

D;D;D;D;D;D;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.0010

D;T;T;D;T;T;T

Sift4G

Uncertain

0.0050

D;T;T;D;D;T;T

Polyphen

0.42, 1.0

.;B;D;.;.;D;B

Vest4

0.90

MutPred

0.56

Gain of phosphorylation at S116 (P = 0.0798);Gain of phosphorylation at S116 (P = 0.0798);Gain of phosphorylation at S116 (P = 0.0798);Gain of phosphorylation at S116 (P = 0.0798);Gain of phosphorylation at S116 (P = 0.0798);Gain of phosphorylation at S116 (P = 0.0798);Gain of phosphorylation at S116 (P = 0.0798);

MVP

0.57

MPC

1.0

ClinPred

0.99

GERP RS

5.5

Varity_R

0.43

gMVP

0.86

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over