chr5-153490969-C-A

Variant names:

• chr5-153490969-C-A
• rs150205263
• NM_000827.4:c.81C>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_000827.4(GRIA1):​c.81C>A​(p.Ile27Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00582 in 1,613,820 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0058 (59 hom.)
• Consequence: GRIA1 NM_000827.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.003172
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.49
• Publications: 2 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• complex neurodevelopmental disorder

  Inheritance: AD, AR Classification: MODERATE, LIMITED Submitted by: ClinGen
• 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 5-153490969-C-A is Benign according to our data. Variant chr5-153490969-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 717700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.49 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000827.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA1	NM_000827.4	MANE Select	c.81C>A	p.Ile27Ile	splice_region synonymous	Exon 1 of 16	NP_000818.2	P42261-1
	GRIA1	NM_001258020.2		c.-262C>A		splice_region	Exon 1 of 17	NP_001244949.1
	GRIA1	NM_001114183.2		c.81C>A	p.Ile27Ile	splice_region synonymous	Exon 1 of 16	NP_001107655.1	P42261-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA1	ENST00000285900.10	TSL:1 MANE Select	c.81C>A	p.Ile27Ile	splice_region synonymous	Exon 1 of 16	ENSP00000285900.4	P42261-1
	GRIA1	ENST00000340592.10	TSL:1	c.81C>A	p.Ile27Ile	splice_region synonymous	Exon 1 of 16	ENSP00000339343.5	P42261-2
	GRIA1	ENST00000481559.6	TSL:1	n.223+1132C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00650 AC: 988 AN: 152094 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0367

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00762

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00661 AC: 1661 AN: 251206 AF XY: 0.00658

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00953

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0324

Gnomad NFE exome AF: 0.00646

Gnomad OTH exome AF: 0.00620

GnomAD4 exome AF: 0.00575 AC: 8408 AN: 1461608 Hom.: 59 Cov.: 30 AF XY: 0.00582 AC XY: 4230 AN XY: 727130

African (AFR) AF: 0.000598 AC: 20 AN: 33472

American (AMR) AF: 0.00127 AC: 57 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00926 AC: 242 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00121 AC: 104 AN: 86252

European-Finnish (FIN) AF: 0.0298 AC: 1593 AN: 53420

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5758

European-Non Finnish (NFE) AF: 0.00549 AC: 6104 AN: 1111768

Other (OTH) AF: 0.00465 AC: 281 AN: 60384

GnomAD4 genome AF: 0.00649 AC: 988 AN: 152212 Hom.: 5 Cov.: 31 AF XY: 0.00763 AC XY: 568 AN XY: 74408

African (AFR) AF: 0.000602 AC: 25 AN: 41548

American (AMR) AF: 0.000784 AC: 12 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.0367 AC: 389 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00762 AC: 518 AN: 68010

Other (OTH) AF: 0.00380 AC: 8 AN: 2108

Alfa AF: 0.00592 Hom.: 8

Bravo AF: 0.00345

EpiCase AF: 0.00649

EpiControl AF: 0.00379

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Benign	0.84
PhyloP100		3.5
PromoterAI		-0.15	Neutral
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0032
dbscSNV1_RF	Benign	0.16
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

Other links and lift over

dbSNP: rs150205263; hg19: chr5-152870529;