9-137156676-G-C

Position:

chr9-137156676-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP2PP5_Very_Strong

The ENST00000371561.8(GRIN1):c.679G>C(p.Asp227His) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,448,130 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D227N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GRIN1
ENST00000371561.8 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.22

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:

GRIN1 (HGNC:):

GRIN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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.

PP5

Variant 9-137156676-G-C is Pathogenic according to our data. Variant chr9-137156676-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137156676-G-C is described in Lovd as [Likely_pathogenic]. Variant chr9-137156676-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIN1	NM_007327.4 linkuse as main transcript	c.679G>C	p.Asp227His	missense_variant	5/20	ENST00000371561.8	NP_015566.1	Q05586-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIN1	ENST00000371561.8 linkuse as main transcript	c.679G>C	p.Asp227His	missense_variant	5/20	1	NM_007327.4	ENSP00000360616.3		Q05586-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1448130

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719300

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:

9.03e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 8;C4693325:Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

Apr 05, 2016

- -

NEURODEVELOPMENTAL DISORDER WITH HYPERKINETIC MOVEMENTS WITH OR WITHOUT SEIZURES, AUTOSOMAL RECESSIVE

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 28, 2022

- -

Intellectual disability, autosomal dominant 8

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Sep 09, 2015

This study shows that diverse genetic causes underlie CVI. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.82

D;.;.;T;.;.;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.95

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

M_CAP

Pathogenic

0.79

MetaRNN

Uncertain

0.64

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

MetaSVM

Uncertain

0.51

MutationAssessor

Benign

1.6

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

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-4.8

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

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0050

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

Polyphen

1.0

D;D;.;.;.;D;.

Vest4

0.45

MutPred

0.58

Loss of phosphorylation at T230 (P = 0.1275);Loss of phosphorylation at T230 (P = 0.1275);.;.;.;Loss of phosphorylation at T230 (P = 0.1275);.;

MVP

0.83

MPC

2.6

ClinPred

0.99

GERP RS

3.3

Varity_R

0.81

gMVP

0.97

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

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