rs778196924

chr9-137158508-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2 PP2 BP4 BP6_Moderate

The NM_007327.4(GRIN1):c.1098C>G(p.Ile366Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GRIN1 NM_007327.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.177

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]

LOC105376328 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GRIN1
• BP4: Computational evidence support a benign effect (MetaRNN=0.26937798).
• BP6: Variant 9-137158508-C-G is Benign according to our data. Variant chr9-137158508-C-G is described in ClinVar as [Benign]. Clinvar id is 580864.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN1	NM_007327.4	c.1098C>G	p.Ile366Met	missense_variant	7/20	ENST00000371561.8
LOC105376328	XR_007061876.1	n.1421G>C		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN1	ENST00000371561.8	c.1098C>G	p.Ile366Met	missense_variant	7/20	1	NM_007327.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250320 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135792

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: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460528 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726562

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Sep 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
Cadd	Uncertain	25
Dann	Benign	0.90
DEOGEN2	Benign	0.27	T;.;.;T;.;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.049
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.27	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;.;.;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.24	N;N;N;N;N;N;N
REVEL	Benign	0.050
Sift	Benign	0.22	T;T;T;T;T;T;T
Sift4G	Benign	0.24	T;T;T;T;T;T;T
Polyphen		0.21	B;B;.;.;.;B;.
Vest4		0.39
MutPred		0.57		Loss of catalytic residue at I366 (P = 0.0019);Loss of catalytic residue at I366 (P = 0.0019);.;.;.;Loss of catalytic residue at I366 (P = 0.0019);.;
MVP		0.44
MPC		1.7
ClinPred		0.19	T
GERP RS		3.4
Varity_R		0.11
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs778196924; hg19: chr9-140052960;