chr9-137163794-G-A

Variant names:

• chr9-137163794-G-A
• rs1451230055
• NM_007327.4:c.2479G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_007327.4(GRIN1):​c.2479G>A​(p.Gly827Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G827G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRIN1 NM_007327.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.43
• Publications: 12 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: G2P, Labcorp Genetics (formerly Invitae), 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: Ambry Genetics, G2P
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_007327.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 9-137163794-G-A is Pathogenic according to our data. Variant chr9-137163794-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 487503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2479G>A	p.Gly827Arg	missense	Exon 18 of 20	NP_015566.1	Q05586-1
	GRIN1	NM_001437330.1		c.2542G>A	p.Gly848Arg	missense	Exon 19 of 21	NP_001424259.1
	GRIN1	NM_001185090.2		c.2542G>A	p.Gly848Arg	missense	Exon 19 of 21	NP_001172019.1	Q05586-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN1	ENST00000371561.8	TSL:1 MANE Select	c.2479G>A	p.Gly827Arg	missense	Exon 18 of 20	ENSP00000360616.3	Q05586-1
	GRIN1	ENST00000371553.8	TSL:1	c.2542G>A	p.Gly848Arg	missense	Exon 19 of 21	ENSP00000360608.3	Q05586-6
	GRIN1	ENST00000371560.5	TSL:1	c.2542G>A	p.Gly848Arg	missense	Exon 19 of 20	ENSP00000360615.3	Q05586-7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250736 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant (2)
2	-	-	not provided (2)
1	-	-	Neurodevelopmental disorder (1)
1	-	-	NEURODEVELOPMENTAL DISORDER WITH HYPERKINETIC MOVEMENTS AND WITH OR WITHOUT SEIZURES, AUTOSOMAL DOMINANT (1)
1	-	-	Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant;C4693325:Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive;C5676955:Developmental and epileptic encephalopathy 101 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.4
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.94		Gain of MoRF binding (P = 0.0139)
MVP		0.95
MPC		3.7
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1451230055; hg19: chr9-140058246; COSMIC: COSV59292292; COSMIC: COSV59292292;