rs878853143

Positions:

• chr9-137162209-C-G
• chr9-137162209-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_007327.4(GRIN1):​c.1670C>G​(p.Pro557Arg) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRIN1 NM_007327.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.26

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GRIN1. . Gene score misZ 6.2157 (greater than the threshold 3.09). Trascript score misZ 6.6419 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.96
• PP5: Variant 9-137162209-C-G is Pathogenic according to our data. Variant chr9-137162209-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 235846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137162209-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIN1	NM_007327.4	c.1670C>G	p.Pro557Arg	missense_variant	12/20	ENST00000371561.8	NP_015566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIN1	ENST00000371561.8	c.1670C>G	p.Pro557Arg	missense_variant	12/20	1	NM_007327.4	ENSP00000360616.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 25, 2023

Published functional studies demonstrate reduced current amplitudes and reduced protein expression when co-expressed with subunits of the N-methyl-D-aspartate receptor (Ogden et al., 2017); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25167861, 28095420, 27164704) -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Jul 25, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;T;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Pathogenic	3.6	H;H;.;.;.;H;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.8	D;D;D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;.;D;.
Vest4		0.98
MutPred		0.82		Gain of methylation at P557 (P = 0.0478);Gain of methylation at P557 (P = 0.0478);.;.;.;Gain of methylation at P557 (P = 0.0478);.;
MVP		0.92
MPC		3.4
ClinPred		1.0	D
GERP RS		3.8
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: rs878853143; hg19: chr9-140056661;