rs1060500046

Variant names:

• chr9-137162649-G-A
• rs1060500046
• NM_007327.4:c.1923G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_007327.4(GRIN1):​c.1923G>A​(p.Met641Ile) 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRIN1 NM_007327.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:2
• Conservation: PhyloP100: 9.58

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.

• PM1: In a transmembrane_region Helical (size 16) in uniprot entity NMDZ1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_007327.4
• 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, 0.938
• PP5: Variant 9-137162649-G-A is Pathogenic according to our data. Variant chr9-137162649-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 403957.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-137162649-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN1	NM_007327.4	c.1923G>A	p.Met641Ile	missense_variant	Exon 14 of 20	ENST00000371561.8	NP_015566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN1	ENST00000371561.8	c.1923G>A	p.Met641Ile	missense_variant	Exon 14 of 20	1	NM_007327.4	ENSP00000360616.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 8 Pathogenic:1

Feb 11, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine with isoleucine at codon 641 of the GRIN1 protein (p.Met641Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals affected with early onset epileptic encephalopathy (PMID: 27164704, Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Met641 amino acid residue in GRIN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30355546, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

GRIN1-related disorder Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as pathogenic and reported on 05/15/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not provided Other:1

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Institute of experimental medicine CAS – Neurochemistry department., Institute of Experimental Medicine, Czech Academy of Science

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

The M641I variant has been identified in patient with sever intellectual disability, movement disorder and seizures (Lemke et al., 2016, PMID: 27164704) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.;.;D;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	2.0	M;M;.;.;.;M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.3	D;D;D;D;D;D;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0060	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D;D;D
Polyphen		0.99	D;D;.;.;.;D;.
Vest4		0.88
MutPred		0.80		Loss of MoRF binding (P = 0.1021);Loss of MoRF binding (P = 0.1021);.;.;.;Loss of MoRF binding (P = 0.1021);.;
MVP		0.77
MPC		3.5
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.92
gMVP		0.99

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: rs1060500046; hg19: chr9-140057101;