chr9-137163642-C-T

Position:

• chr9-137163642-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PM1 PM2 PM5 PP2 PP5 BP4

The NM_007327.4(GRIN1):​c.2417C>T​(p.Ala806Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A806E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRIN1 NM_007327.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 5.47

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr9-137163642-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522682.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 9-137163642-C-T is Pathogenic according to our data. Variant chr9-137163642-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 810481.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3340088). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN1	NM_007327.4	c.2417C>T	p.Ala806Val	missense_variant	17/20	ENST00000371561.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN1	ENST00000371561.8	c.2417C>T	p.Ala806Val	missense_variant	17/20	1	NM_007327.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 8 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 02, 2021	PS2, PM2, PM1 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 20, 2023	- -

GRIN1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 19, 2023

The GRIN1 c.2417C>T variant is predicted to result in the amino acid substitution p.Ala806Val. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D;.;.;D;.;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.1	M;M;.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D
REVEL	Benign	0.21
Sift	Uncertain	0.020	D;D;D;D;D;D;D
Sift4G	Benign	0.061	T;T;T;T;D;T;T
Polyphen		0.99	D;D;.;.;.;D;.
Vest4		0.31
MutPred		0.39		Loss of disorder (P = 0.0517);Loss of disorder (P = 0.0517);.;.;.;Loss of disorder (P = 0.0517);.;
MVP		0.68
MPC		3.2
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.60
gMVP		0.96

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: rs1554770589; hg19: chr9-140058094;