rs2963954

Variant names:

• chr5-153645021-T-C
• rs2963954
• NM_000827.4:c.221-1907T>C

Variant summary

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

The NM_000827.4(GRIA1):​c.221-1907T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.555 in 151,656 control chromosomes in the GnomAD database, including 24,060 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.

• Frequency: Genomes: 𝑓 0.56 (24060 hom., cov: 30)
• Consequence: GRIA1 NM_000827.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.00
• Publications: 3 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.595 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIA1	NM_000827.4	c.221-1907T>C		intron_variant	Intron 2 of 15	ENST00000285900.10	NP_000818.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIA1	ENST00000285900.10	c.221-1907T>C		intron_variant	Intron 2 of 15	1	NM_000827.4	ENSP00000285900.4

Frequencies

GnomAD3 genomes AF: 0.555 AC: 84116 AN: 151536 Hom.: 24031 Cov.: 30

Gnomad AFR AF: 0.560

Gnomad AMI AF: 0.653

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.609

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.602

Gnomad NFE AF: 0.600

Gnomad OTH AF: 0.559

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.555 AC: 84196 AN: 151656 Hom.: 24060 Cov.: 30 AF XY: 0.548 AC XY: 40596 AN XY: 74084

African (AFR) AF: 0.561 AC: 23149 AN: 41294

American (AMR) AF: 0.486 AC: 7400 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 2115 AN: 3472

East Asian (EAS) AF: 0.148 AC: 759 AN: 5116

South Asian (SAS) AF: 0.442 AC: 2130 AN: 4814

European-Finnish (FIN) AF: 0.569 AC: 5960 AN: 10468

Middle Eastern (MID) AF: 0.596 AC: 174 AN: 292

European-Non Finnish (NFE) AF: 0.600 AC: 40747 AN: 67956

Other (OTH) AF: 0.553 AC: 1168 AN: 2112

Alfa AF: 0.582 Hom.: 13088

Bravo AF: 0.549

Asia WGS AF: 0.299 AC: 1041 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.78
DANN	Benign	0.62
PhyloP100		-1.0
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: rs2963954; hg19: chr5-153024581;