chr11-105611049-C-G

Position:

• chr11-105611049-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 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=0.009750307).
• 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 GnomAd4 at 184 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;