9-137163606-G-T

Position:

• chr9-137163606-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP2 BP4

The NM_007327.4(GRIN1):​c.2381G>T​(p.Arg794Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R794Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRIN1 NM_007327.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.33

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 6 ACMG points.

• PM1: In a disulfide_bond (size 54) in uniprot entity NMDZ1_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) 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 chr9-137163606-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 435376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, GRIN1
• BP4: Computational evidence support a benign effect (MetaRNN=0.38070315).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN1	NM_007327.4	c.2381G>T	p.Arg794Leu	missense_variant	17/20	ENST00000371561.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN1	ENST00000371561.8	c.2381G>T	p.Arg794Leu	missense_variant	17/20	1	NM_007327.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D;.;.;T;.;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.7	L;L;.;.;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.6	D;D;D;D;D;D;D
REVEL	Benign	0.19
Sift	Benign	0.43	T;T;T;T;T;T;T
Sift4G	Benign	0.40	T;T;T;T;T;T;T
Polyphen		0.97	D;D;.;.;.;D;.
Vest4		0.50
MutPred		0.45		Loss of disorder (P = 0.0587);Loss of disorder (P = 0.0587);.;.;.;Loss of disorder (P = 0.0587);.;
MVP		0.80
MPC		3.6
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.76
gMVP		0.98

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: rs781053477; hg19: chr9-140058058;