NM_007327.4:c.2231G>A

Variant names:

• chr9-137163228-G-A
• rs1554770444
• NM_007327.4:c.2231G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_007327.4(GRIN1):​c.2231G>A​(p.Cys744Tyr) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRIN1 NM_007327.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.31

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the GRIN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 75 curated pathogenic missense variants (we use a threshold of 10). The gene has 49 curated benign missense variants. Gene score misZ: 6.2157 (above the threshold of 3.09). Trascript score misZ: 6.6419 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental and epileptic encephalopathy 101, neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, autosomal dominant non-syndromic intellectual disability, complex neurodevelopmental disorder, intellectual disability, autosomal dominant 8.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 9-137163228-G-A is Pathogenic according to our data. Variant chr9-137163228-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 539840.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-137163228-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN1	NM_007327.4	c.2231G>A	p.Cys744Tyr	missense_variant	Exon 16 of 20	ENST00000371561.8	NP_015566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN1	ENST00000371561.8	c.2231G>A	p.Cys744Tyr	missense_variant	Exon 16 of 20	1	NM_007327.4	ENSP00000360616.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 8 Pathogenic:1

Jul 14, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;D;.;.;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.9	H;H;.;.;.;H;.
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-9.8	D;D;D;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;.;D;.
Vest4		0.97
MutPred		0.89		Loss of methylation at K743 (P = 0.0203);Loss of methylation at K743 (P = 0.0203);.;.;.;Loss of methylation at K743 (P = 0.0203);.;
MVP		0.92
MPC		5.0
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.99
gMVP		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554770444; hg19: chr9-140057680;