rs771610568

Variant names:

• chr9-137162676-C-A
• NM_007327.4:c.1950C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-137162676-C-A
• chr9-137162676-C-G
• chr9-137162676-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_007327.4(GRIN1):​c.1950C>A​(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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. 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 criteria provided, single submitter P: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 15 ACMG points.

• PS1: Transcript NM_007327.4 (GRIN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• 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 Lovd as [Pathogenic].
• 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, 0.988
• PP5: Variant 9-137162676-C-A is Pathogenic according to our data. Variant chr9-137162676-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1329920.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN1	NM_007327.4	c.1950C>A	p.Asn650Lys	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.1950C>A	p.Asn650Lys	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

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 8 Pathogenic:1

Sep 04, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS1, PM5_STR, PS2_MOD, PM1, PM2_SUP, PP3 -

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	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;.;D;.;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.82	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;.
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)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-140057128;