11-105611049-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_000829.4(GRIA4):c.52C>G(p.Leu18Val) variant causes a missense change. The variant allele was found at a frequency of 0.000228 in 1,613,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: GRIA4 NM_000829.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.17

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 Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GRIA4
• BP4: Computational evidence support a benign effect (MetaRNN=0.009750307).
• BP6: Variant 11-105611049-C-G is Benign according to our data. Variant chr11-105611049-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3048830.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 183 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIA4	NM_000829.4	c.52C>G	p.Leu18Val	missense_variant	2/17	ENST00000282499.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIA4	ENST00000282499.10	c.52C>G	p.Leu18Val	missense_variant	2/17	5	NM_000829.4	A1

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 183 AN: 151992 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00406

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000330 AC: 83 AN: 251466 Hom.: 0 AF XY: 0.000302 AC XY: 41 AN XY: 135902

Gnomad AFR exome AF: 0.00394

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000126 AC: 184 AN: 1461558 Hom.: 0 Cov.: 30 AF XY: 0.000121 AC XY: 88 AN XY: 727084

Gnomad4 AFR exome AF: 0.00323

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.00121 AC: 184 AN: 152108 Hom.: 0 Cov.: 29 AF XY: 0.00110 AC XY: 82 AN XY: 74344

Gnomad4 AFR AF: 0.00407

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000674 Hom.: 0

Bravo AF: 0.00129

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000412 AC: 50

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

GRIA4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 23, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	22
Dann	Uncertain	0.98
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0098	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.91	N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.046, 0.077	.;.;.;B;B;.;.;.;.;B;B
Vest4		0.69, 0.68, 0.68, 0.71, 0.62, 0.69, 0.69
MVP		0.49
MPC		0.26
ClinPred		0.059	T
GERP RS		4.9
Varity_R		0.32
gMVP		0.37

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: rs79495463; hg19: chr11-105481776;