rs609239

Positions:

• chr11-105898257-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000829.4(GRIA4):​c.727-12T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0899 in 1,388,728 control chromosomes in the GnomAD database, including 6,645 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.095 (849 hom., cov: 32)
  • Exomes 𝑓: 0.089 (5796 hom.)
• Consequence: GRIA4 NM_000829.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003433
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.261

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 -12 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 3 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIA4	NM_000829.4	c.727-12T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000282499.10	NP_000820.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIA4	ENST00000282499.10	c.727-12T>C		splice_polypyrimidine_tract_variant, intron_variant		5	NM_000829.4	ENSP00000282499	A1

Frequencies

GnomAD3 genomes AF: 0.0947 AC: 14401 AN: 151994 Hom.: 847 Cov.: 32

Gnomad AFR AF: 0.0694

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.0619

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0819

Gnomad OTH AF: 0.129

GnomAD3 exomes AF: 0.110 AC: 25242 AN: 229484 Hom.: 1862 AF XY: 0.103 AC XY: 12923 AN XY: 124976

Gnomad AFR exome AF: 0.0655

Gnomad AMR exome AF: 0.246

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.176

Gnomad SAS exome AF: 0.0601

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.0819

Gnomad OTH exome AF: 0.109

GnomAD4 exome AF: 0.0892 AC: 110362 AN: 1236616 Hom.: 5796 Cov.: 17 AF XY: 0.0878 AC XY: 54869 AN XY: 624666

Gnomad4 AFR exome AF: 0.0610

Gnomad4 AMR exome AF: 0.238

Gnomad4 ASJ exome AF: 0.146

Gnomad4 EAS exome AF: 0.144

Gnomad4 SAS exome AF: 0.0603

Gnomad4 FIN exome AF: 0.0997

Gnomad4 NFE exome AF: 0.0818

Gnomad4 OTH exome AF: 0.0956

GnomAD4 genome AF: 0.0949 AC: 14428 AN: 152112 Hom.: 849 Cov.: 32 AF XY: 0.0966 AC XY: 7183 AN XY: 74388

Gnomad4 AFR AF: 0.0698

Gnomad4 AMR AF: 0.186

Gnomad4 ASJ AF: 0.149

Gnomad4 EAS AF: 0.159

Gnomad4 SAS AF: 0.0611

Gnomad4 FIN AF: 0.106

Gnomad4 NFE AF: 0.0819

Gnomad4 OTH AF: 0.129

Alfa AF: 0.0911 Hom.: 168

Bravo AF: 0.103

Asia WGS AF: 0.100 AC: 345 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.1
DANN	Benign	0.56
BranchPoint Hunter		3.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0
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: rs609239; hg19: chr11-105768983; COSMIC: COSV56879776;