11-105611080-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP6_Moderate

The NM_000829.4(GRIA4):c.83A>C(p.Gln28Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,120 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GRIA4 NM_000829.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 8.47

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GRIA4
• BP6: Variant 11-105611080-A-C is Benign according to our data. Variant chr11-105611080-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2429908.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIA4	NM_000829.4	c.83A>C	p.Gln28Pro	missense_variant	2/17	ENST00000282499.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIA4	ENST00000282499.10	c.83A>C	p.Gln28Pro	missense_variant	2/17	5	NM_000829.4	A1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459120 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726086

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autism spectrum disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Aug 16, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
Cadd	Uncertain	24
Dann	Benign	0.33
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.3	D;N;D;N;N;D;D;N;N;N;N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0070	D;T;D;T;T;D;D;T;T;T;T
Sift4G	Uncertain	0.025	D;D;D;T;T;T;D;D;D;T;T
Polyphen		0.0, 0.68	.;.;.;B;P;.;.;.;.;P;B
Vest4		0.90, 0.90, 0.91, 0.91, 0.88, 0.90
MVP		0.84
MPC		0.63
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.46
gMVP		0.91

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: rs150577695; hg19: chr11-105481807;