NM_007327.4:c.679G>A

Variant names:

• chr9-137156676-G-A
• rs869312865
• NM_007327.4:c.679G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_007327.4(GRIN1):​c.679G>A​(p.Asp227Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,448,130 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D227H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GRIN1 NM_007327.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.22
• Publications: 2 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

LOC105376328 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-137156676-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 224815.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.679G>A	p.Asp227Asn	missense	Exon 5 of 20	NP_015566.1	Q05586-1
	GRIN1	NM_001437330.1		c.742G>A	p.Asp248Asn	missense	Exon 6 of 21	NP_001424259.1
	GRIN1	NM_001185090.2		c.742G>A	p.Asp248Asn	missense	Exon 6 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.679G>A	p.Asp227Asn	missense	Exon 5 of 20	ENSP00000360616.3	Q05586-1
	GRIN1	ENST00000371553.8	TSL:1	c.742G>A	p.Asp248Asn	missense	Exon 6 of 21	ENSP00000360608.3	Q05586-6
	GRIN1	ENST00000371560.5	TSL:1	c.742G>A	p.Asp248Asn	missense	Exon 6 of 20	ENSP00000360615.3	Q05586-7

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000446 AC: 1 AN: 224368 AF XY: 0.00000819

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: 0.0000101

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1448130 Hom.: 0 Cov.: 34 AF XY: 0.00000139 AC XY: 1 AN XY: 719300

African (AFR) AF: 0.00 AC: 0 AN: 33250

American (AMR) AF: 0.00 AC: 0 AN: 43508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25854

East Asian (EAS) AF: 0.00 AC: 0 AN: 39110

South Asian (SAS) AF: 0.00 AC: 0 AN: 84130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5368

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1106914

Other (OTH) AF: 0.00 AC: 0 AN: 59784

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	1.6	L
PhyloP100		6.2
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.013	D
Polyphen		0.99	D
Vest4		0.48
MutPred		0.55		Loss of phosphorylation at T230 (P = 0.1362)
MVP		0.81
MPC		2.3
ClinPred		0.95	D
GERP RS		3.3
Varity_R		0.67
gMVP		0.96
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs869312865; hg19: chr9-140051128; COSMIC: COSV104634782; COSMIC: COSV104634782;