5-153492228-T-TC

Variant names:

• chr5-153492228-T-TC
• rs3841128
• NM_000827.4:c.82+1259dupC

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 4P and 10B. PVS1_Strong BP6_Moderate BA1

The NM_001258021.2(GRIA1):​c.31dupC​(p.Leu11ProfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.036 in 1,535,256 control chromosomes in the GnomAD database, including 3,243 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.086 (1195 hom., cov: 31)
  • Exomes 𝑓: 0.030 (2048 hom.)
• Consequence: GRIA1 NM_001258021.2 frameshift
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.645

Genes affected

GRIA1 (HGNC:4571): (glutamate ionotropic receptor AMPA type subunit 1) 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 with multiple subunits, each possessing transmembrane regions, and all arranged to form a ligand-gated ion channel. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. This gene belongs to a family of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
• BP6: Variant 5-153492228-T-TC is Benign according to our data. Variant chr5-153492228-T-TC is described in ClinVar as [Benign]. Clinvar id is 218567.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIA1	NM_000827.4	c.82+1259dupC		intron_variant	Intron 1 of 15	ENST00000285900.10	NP_000818.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIA1	ENST00000285900.10	c.82+1259dupC		intron_variant	Intron 1 of 15	1	NM_000827.4	ENSP00000285900.4

Frequencies

GnomAD3 genomes AF: 0.0859 AC: 13069 AN: 152080 Hom.: 1189 Cov.: 31

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.0371

Gnomad ASJ AF: 0.0426

Gnomad EAS AF: 0.0436

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.0490

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0188

Gnomad OTH AF: 0.0757

GnomAD3 exomes AF: 0.0502 AC: 6434 AN: 128232 Hom.: 408 AF XY: 0.0533 AC XY: 3744 AN XY: 70202

Gnomad AFR exome AF: 0.242

Gnomad AMR exome AF: 0.0187

Gnomad ASJ exome AF: 0.0495

Gnomad EAS exome AF: 0.0397

Gnomad SAS exome AF: 0.114

Gnomad FIN exome AF: 0.0406

Gnomad NFE exome AF: 0.0167

Gnomad OTH exome AF: 0.0356

GnomAD4 exome AF: 0.0305 AC: 42139 AN: 1383058 Hom.: 2048 Cov.: 31 AF XY: 0.0325 AC XY: 22152 AN XY: 682426

Gnomad4 AFR exome AF: 0.243

Gnomad4 AMR exome AF: 0.0216

Gnomad4 ASJ exome AF: 0.0468

Gnomad4 EAS exome AF: 0.0763

Gnomad4 SAS exome AF: 0.113

Gnomad4 FIN exome AF: 0.0410

Gnomad4 NFE exome AF: 0.0156

Gnomad4 OTH exome AF: 0.0407

GnomAD4 genome AF: 0.0861 AC: 13097 AN: 152198 Hom.: 1195 Cov.: 31 AF XY: 0.0870 AC XY: 6472 AN XY: 74410

Gnomad4 AFR AF: 0.231

Gnomad4 AMR AF: 0.0371

Gnomad4 ASJ AF: 0.0426

Gnomad4 EAS AF: 0.0439

Gnomad4 SAS AF: 0.114

Gnomad4 FIN AF: 0.0490

Gnomad4 NFE AF: 0.0188

Gnomad4 OTH AF: 0.0744

Alfa AF: 0.0228 Hom.: 55

Bravo AF: 0.0912

Asia WGS AF: 0.0880 AC: 304 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 16, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GRIA1-related disorder Benign:1

Nov 29, 2023

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3841128; hg19: chr5-152871788;