rs781053477

Positions:

• chr9-137163606-G-A
• chr9-137163606-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 15P and 1B. PM1 PM2 PM5 PP2 PP5_Very_Strong BP4

The NM_007327.4(GRIN1):​c.2381G>A​(p.Arg794Gln) 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 benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R794G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRIN1 NM_007327.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.33

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 Pathogenic. Variant got 14 ACMG points.

• PM1: In a disulfide_bond (size 54) in uniprot entity NMDZ1_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_007327.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-137163605-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1481271.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, GRIN1
• PP5: Variant 9-137163606-G-A is Pathogenic according to our data. Variant chr9-137163606-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 435376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137163606-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.33147436). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN1	NM_007327.4	c.2381G>A	p.Arg794Gln	missense_variant	17/20	ENST00000371561.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN1	ENST00000371561.8	c.2381G>A	p.Arg794Gln	missense_variant	17/20	1	NM_007327.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 8 Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Feb 02, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 28, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 25, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GRIN1 function (PMID: 29365063). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GRIN1 protein function. ClinVar contains an entry for this variant (Variation ID: 435376). This missense change has been observed in individual(s) with clinical features of GRIN1-related conditions (PMID: 29365063). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 794 of the GRIN1 protein (p.Arg794Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;.;T;.;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.1	L;L;.;.;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.53	T;T;T;T;T;T;T
Sift4G	Benign	0.59	T;T;T;T;T;T;T
Polyphen		1.0	D;D;.;.;.;D;.
Vest4		0.33
MutPred		0.43		Gain of methylation at K790 (P = 0.0564);Gain of methylation at K790 (P = 0.0564);.;.;.;Gain of methylation at K790 (P = 0.0564);.;
MVP		0.81
MPC		3.3
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.63
gMVP		0.95

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: rs781053477; hg19: chr9-140058058;