rs707176

Positions:

• chr5-153650400-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_000827.4(GRIA1):​c.531T>C​(p.Ile177=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 1,613,532 control chromosomes in the GnomAD database, including 79,191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (5962 hom., cov: 31)
  • Exomes 𝑓: 0.31 (73229 hom.)
• Consequence: GRIA1 NM_000827.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.861

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 5-153650400-T-C is Benign according to our data. Variant chr5-153650400-T-C is described in ClinVar as [Benign]. Clinvar id is 3059187.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.861 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.336 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIA1	NM_000827.4	c.531T>C	p.Ile177=	synonymous_variant	4/16	ENST00000285900.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIA1	ENST00000285900.10	c.531T>C	p.Ile177=	synonymous_variant	4/16	1	NM_000827.4	P3

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39500 AN: 151944 Hom.: 5962 Cov.: 31

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.0255

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.326

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.339

Gnomad OTH AF: 0.260

GnomAD3 exomes AF: 0.260 AC: 65161 AN: 250988 Hom.: 9852 AF XY: 0.260 AC XY: 35240 AN XY: 135626

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.233

Gnomad ASJ exome AF: 0.286

Gnomad EAS exome AF: 0.0305

Gnomad SAS exome AF: 0.141

Gnomad FIN exome AF: 0.330

Gnomad NFE exome AF: 0.337

Gnomad OTH exome AF: 0.284

GnomAD4 exome AF: 0.307 AC: 448063 AN: 1461468 Hom.: 73229 Cov.: 35 AF XY: 0.302 AC XY: 219935 AN XY: 727068

Gnomad4 AFR exome AF: 0.144

Gnomad4 AMR exome AF: 0.241

Gnomad4 ASJ exome AF: 0.286

Gnomad4 EAS exome AF: 0.0182

Gnomad4 SAS exome AF: 0.141

Gnomad4 FIN exome AF: 0.331

Gnomad4 NFE exome AF: 0.338

Gnomad4 OTH exome AF: 0.291

GnomAD4 genome AF: 0.260 AC: 39507 AN: 152064 Hom.: 5962 Cov.: 31 AF XY: 0.254 AC XY: 18894 AN XY: 74324

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.269

Gnomad4 ASJ AF: 0.291

Gnomad4 EAS AF: 0.0255

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.326

Gnomad4 NFE AF: 0.339

Gnomad4 OTH AF: 0.256

Alfa AF: 0.318 Hom.: 10328

Bravo AF: 0.253

Asia WGS AF: 0.0900 AC: 316 AN: 3478

EpiCase AF: 0.332

EpiControl AF: 0.333

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

GRIA1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 29, 2023

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

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.8
DANN	Benign	0.83

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: rs707176; hg19: chr5-153029960; COSMIC: COSV53616674;