9-137162676-C-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_007327.4(GRIN1):c.1950C>G(p.Asn650Lys) variant causes a missense change involving the alteration of a non-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 (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N650I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRIN1 NM_007327.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 1.89

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 16 ACMG points.

• PS1: Transcript NM_007327.4 (GRIN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 1329920
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain 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 chr9-137162675-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 429784.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, GRIN1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 9-137162676-C-G is Pathogenic according to our data. Variant chr9-137162676-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 487502.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-137162676-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN1	NM_007327.4	c.1950C>G	p.Asn650Lys	missense_variant	14/20	ENST00000371561.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN1	ENST00000371561.8	c.1950C>G	p.Asn650Lys	missense_variant	14/20	1	NM_007327.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, autosomal dominant 8 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 09, 2018

- -

not provided Other:1

not provided, no classification provided

in vitro

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

-

The N650K variant has been reported in patient with severe developmental delay and seizures. Patient showed hand-washing, hand-wringing, hand-mouthing stereotypical movements, dyskinesia, bruxism (Lemke et al., 2016 PMID: 27164704; Ohba et al., 2015 PMID: 25864721). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;.;D;.;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.2	M;M;.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.7	D;D;D;D;D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;.;D;.
Vest4		0.97
MutPred		0.92		Gain of ubiquitination at N650 (P = 0.0185);Gain of ubiquitination at N650 (P = 0.0185);.;.;.;Gain of ubiquitination at N650 (P = 0.0185);.;
MVP		0.87
MPC		3.6
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.98
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs771610568; hg19: chr9-140057128;