rs1126442

Variant names:

• chr9-137156924-G-A
• rs1126442
• NM_007327.4:c.855G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_007327.4(GRIN1):​c.855G>A​(p.Val285Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,611,588 control chromosomes in the GnomAD database, including 76,416 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5431 hom., cov: 34)
  • Exomes 𝑓: 0.30 (70985 hom.)
• Consequence: GRIN1 NM_007327.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.10
• Publications: 18 publications found

Genes affected

GRIN1 (HGNC:4584): (glutamate ionotropic receptor NMDA type subunit 1) The protein encoded by this gene is a critical subunit of N-methyl-D-aspartate receptors, members of the glutamate receptor channel superfamily which are heteromeric protein complexes with multiple subunits arranged to form a ligand-gated ion channel. These subunits play a key role in the plasticity of synapses, which is believed to underlie memory and learning. Cell-specific factors are thought to control expression of different isoforms, possibly contributing to the functional diversity of the subunits. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2008]

GRIN1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, MODERATE Submitted by: G2P, Ambry Genetics
• developmental and epileptic encephalopathy 101

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC105376328 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 9-137156924-G-A is Benign according to our data. Variant chr9-137156924-G-A is described in ClinVar as Benign. ClinVar VariationId is 129183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007327.4. 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
	GRIN1	NM_007327.4	MANE Select	c.855G>A	p.Val285Val	synonymous	Exon 6 of 20	NP_015566.1
	GRIN1	NM_001437330.1		c.918G>A	p.Val306Val	synonymous	Exon 7 of 21	NP_001424259.1
	GRIN1	NM_001185090.2		c.918G>A	p.Val306Val	synonymous	Exon 7 of 21	NP_001172019.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN1	ENST00000371561.8	TSL:1 MANE Select	c.855G>A	p.Val285Val	synonymous	Exon 6 of 20	ENSP00000360616.3
	GRIN1	ENST00000371553.8	TSL:1	c.918G>A	p.Val306Val	synonymous	Exon 7 of 21	ENSP00000360608.3
	GRIN1	ENST00000371560.5	TSL:1	c.918G>A	p.Val306Val	synonymous	Exon 7 of 20	ENSP00000360615.3

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35633 AN: 152146 Hom.: 5430 Cov.: 34

Gnomad AFR AF: 0.0649

Gnomad AMI AF: 0.439

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.215

GnomAD2 exomes AF: 0.259 AC: 62818 AN: 242252 AF XY: 0.264

Gnomad AFR exome AF: 0.0559

Gnomad AMR exome AF: 0.198

Gnomad ASJ exome AF: 0.257

Gnomad EAS exome AF: 0.00165

Gnomad FIN exome AF: 0.415

Gnomad NFE exome AF: 0.331

Gnomad OTH exome AF: 0.289

GnomAD4 exome AF: 0.302 AC: 440036 AN: 1459324 Hom.: 70985 Cov.: 47 AF XY: 0.300 AC XY: 217435 AN XY: 725956

African (AFR) AF: 0.0537 AC: 1798 AN: 33466

American (AMR) AF: 0.197 AC: 8802 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 6829 AN: 26102

East Asian (EAS) AF: 0.00134 AC: 53 AN: 39684

South Asian (SAS) AF: 0.228 AC: 19664 AN: 86206

European-Finnish (FIN) AF: 0.412 AC: 21301 AN: 51714

Middle Eastern (MID) AF: 0.279 AC: 1608 AN: 5762

European-Non Finnish (NFE) AF: 0.327 AC: 363811 AN: 1111448

Other (OTH) AF: 0.268 AC: 16170 AN: 60314

GnomAD4 genome AF: 0.234 AC: 35634 AN: 152264 Hom.: 5431 Cov.: 34 AF XY: 0.236 AC XY: 17580 AN XY: 74448

African (AFR) AF: 0.0647 AC: 2690 AN: 41570

American (AMR) AF: 0.224 AC: 3431 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 886 AN: 3468

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5186

South Asian (SAS) AF: 0.209 AC: 1010 AN: 4824

European-Finnish (FIN) AF: 0.404 AC: 4285 AN: 10608

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.329 AC: 22383 AN: 67986

Other (OTH) AF: 0.213 AC: 450 AN: 2112

Alfa AF: 0.275 Hom.: 5438

Bravo AF: 0.212

Asia WGS AF: 0.0890 AC: 311 AN: 3478

EpiCase AF: 0.318

EpiControl AF: 0.319

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_noAF	Benign	-0.38
CADD	Benign	14
DANN	Benign	0.97
PhyloP100		1.1
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1126442; hg19: chr9-140051376;