rs609239

Variant names:

• chr11-105898257-T-C
• rs609239
• NM_000829.4:c.727-12T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000829.4(GRIA4):​c.727-12T>C variant causes a 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 intron
• Scores: Splicing: ADA: 0.00003433
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.261
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with or without seizures and gait abnormalities

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. 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 rank	MANE	Protein	UniProt
GRIA4	NM_000829.4	c.727-12T>C		intron_variant	Intron 6 of 16	ENST00000282499.10	NP_000820.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIA4	ENST00000282499.10	c.727-12T>C		intron_variant	Intron 6 of 16	5	NM_000829.4	ENSP00000282499.5

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

GnomAD2 exomes AF: 0.110 AC: 25242 AN: 229484 AF XY: 0.103

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 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

African (AFR) AF: 0.0610 AC: 1725 AN: 28294

American (AMR) AF: 0.238 AC: 9011 AN: 37844

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 3462 AN: 23744

East Asian (EAS) AF: 0.144 AC: 5526 AN: 38248

South Asian (SAS) AF: 0.0603 AC: 4570 AN: 75774

European-Finnish (FIN) AF: 0.0997 AC: 5266 AN: 52820

Middle Eastern (MID) AF: 0.0597 AC: 314 AN: 5256

European-Non Finnish (NFE) AF: 0.0818 AC: 75448 AN: 921940

Other (OTH) AF: 0.0956 AC: 5040 AN: 52696

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

African (AFR) AF: 0.0698 AC: 2901 AN: 41540

American (AMR) AF: 0.186 AC: 2845 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 517 AN: 3468

East Asian (EAS) AF: 0.159 AC: 826 AN: 5180

South Asian (SAS) AF: 0.0611 AC: 295 AN: 4826

European-Finnish (FIN) AF: 0.106 AC: 1127 AN: 10600

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0819 AC: 5566 AN: 67922

Other (OTH) AF: 0.129 AC: 272 AN: 2104

Alfa AF: 0.0932 Hom.: 306

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
PhyloP100		0.26
BranchPoint Hunter		3.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs609239; hg19: chr11-105768983; COSMIC: COSV56879776;