11-105611002-G-A

Position:

chr11-105611002-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4BS2_Supporting

The NM_000829.4(GRIA4):c.5G>A(p.Arg2Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,609,296 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

GRIA4
NM_000829.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.25

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 Likely_benign. Variant got -1 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.36345112).

BS2

High AC in GnomAdExome4 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	Protein	UniProt
GRIA4	NM_000829.4 linkuse as main transcript	c.5G>A	p.Arg2Lys	missense_variant	2/17	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.5G>A	p.Arg2Lys	missense_variant	2/17	5	NM_000829.4	ENSP00000282499	A1	P48058-1

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151578

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251390

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000480

AC:

AN:

1457606

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725438

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151690

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74108

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2023

The c.5G>A (p.R2K) alteration is located in exon 2 (coding exon 1) of the GRIA4 gene. This alteration results from a G to A substitution at nucleotide position 5, causing the arginine (R) at amino acid position 2 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

.;.;.;T;.;.;.;.;T;.;T

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.35

.;.;.;T;T;T;T;T;T;.;.

M_CAP

Benign

0.0057

MetaRNN

Benign

0.36

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

.;L;.;L;.;.;.;L;.;.;L

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.41

N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.049

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

Sift4G

Benign

0.30

T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.083, 0.14

.;.;.;B;B;.;.;.;.;B;B

Vest4

0.69, 0.69, 0.65, 0.60, 0.61, 0.57, 0.61

MutPred

0.31

Gain of methylation at R2 (P = 0.0718);Gain of methylation at R2 (P = 0.0718);Gain of methylation at R2 (P = 0.0718);Gain of methylation at R2 (P = 0.0718);Gain of methylation at R2 (P = 0.0718);Gain of methylation at R2 (P = 0.0718);Gain of methylation at R2 (P = 0.0718);Gain of methylation at R2 (P = 0.0718);Gain of methylation at R2 (P = 0.0718);Gain of methylation at R2 (P = 0.0718);Gain of methylation at R2 (P = 0.0718);

MVP

0.47

MPC

0.27

ClinPred

0.25

GERP RS

4.8

Varity_R

0.26

gMVP

0.68

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