NM_007327.4:c.1340C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4

The NM_007327.4(GRIN1):c.1340C>T(p.Pro447Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000411 in 1,460,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

GRIN1
NM_007327.4 missense, splice_region

Scores

Splicing: ADA: 0.03594

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.53

Variant links:

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 links:

LOC105376328 (HGNC:):

LOC105376328 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.2864001).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN1	NM_007327.4 link	c.1340C>T	p.Pro447Leu	missense_variant, splice_region_variant	Exon 10 of 20	ENST00000371561.8	NP_015566.1	Q05586-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN1	ENST00000371561.8 link	c.1340C>T	p.Pro447Leu	missense_variant, splice_region_variant	Exon 10 of 20	1	NM_007327.4	ENSP00000360616.3		Q05586-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000809

AC:

AN:

247074

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134422

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000182

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460026

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726354

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Mar 31, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability, autosomal dominant 8

Uncertain:1

Mar 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 447 of the GRIN1 protein (p.Pro447Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with GRIN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 129178). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä† is likely to be tolerated. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.46

T;.;.;T;.;.;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.91

D;D;D;D;D;D;D

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.29

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;L;.;.;.;L;.

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.4

N;N;D;D;D;N;D

REVEL

Benign

0.094

Sift

Benign

0.16

T;T;T;T;T;T;T

Sift4G

Benign

0.33

T;T;T;T;T;T;T

Polyphen

0.32

B;P;.;.;.;B;.

Vest4

0.16

MutPred

0.48

Loss of glycosylation at P447 (P = 0.018);Loss of glycosylation at P447 (P = 0.018);.;.;.;Loss of glycosylation at P447 (P = 0.018);.;

MVP

0.44

MPC

1.3

ClinPred

0.57

GERP RS

1.9

Varity_R

0.12

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.036

dbscSNV1_RF

Benign

0.34

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over