rs707176

Variant names:

• chr5-153650400-T-C
• rs707176
• NM_000827.4:c.531T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BA1

The NM_000827.4(GRIA1):​c.531T>C​(p.Ile177Ile) 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.26 (5962 hom., cov: 31)
  • Exomes 𝑓: 0.31 (73229 hom.)
• Consequence: GRIA1 NM_000827.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.861
• Publications: 29 publications found

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]

GRIA1 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, autosomal dominant 67

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• intellectual developmental disorder, autosomal recessive 76

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 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 VariationId is 3059187.Status of the report is no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
GRIA1	NM_000827.4	c.531T>C	p.Ile177Ile	synonymous_variant	Exon 4 of 16	ENST00000285900.10	NP_000818.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIA1	ENST00000285900.10	c.531T>C	p.Ile177Ile	synonymous_variant	Exon 4 of 16	1	NM_000827.4	ENSP00000285900.4

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

GnomAD2 exomes AF: 0.260 AC: 65161 AN: 250988 AF XY: 0.260

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 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

African (AFR) AF: 0.144 AC: 4810 AN: 33460

American (AMR) AF: 0.241 AC: 10763 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 7479 AN: 26122

East Asian (EAS) AF: 0.0182 AC: 724 AN: 39682

South Asian (SAS) AF: 0.141 AC: 12194 AN: 86244

European-Finnish (FIN) AF: 0.331 AC: 17671 AN: 53412

Middle Eastern (MID) AF: 0.238 AC: 1369 AN: 5760

European-Non Finnish (NFE) AF: 0.338 AC: 375495 AN: 1111714

Other (OTH) AF: 0.291 AC: 17558 AN: 60372

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

African (AFR) AF: 0.149 AC: 6174 AN: 41502

American (AMR) AF: 0.269 AC: 4101 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1009 AN: 3470

East Asian (EAS) AF: 0.0255 AC: 132 AN: 5176

South Asian (SAS) AF: 0.133 AC: 641 AN: 4810

European-Finnish (FIN) AF: 0.326 AC: 3450 AN: 10574

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.339 AC: 23051 AN: 67944

Other (OTH) AF: 0.256 AC: 541 AN: 2110

Alfa AF: 0.303 Hom.: 15636

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: no assertion criteria provided

Submissions by phenotype

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

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.8
DANN	Benign	0.83
PhyloP100		0.86
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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