rs1057520055

chr9-137162734-C-Achr9-137162734-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PP2 PP3_Moderate PP5_Moderate

The NM_007327.4(GRIN1):c.2008C>A(p.Pro670Thr) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. 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. P670S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GRIN1 NM_007327.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.68

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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_007327.4
• PP2: Missense variant where missense usually causes diseases, GRIN1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853
• PP5: Variant 9-137162734-C-A is Pathogenic according to our data. Variant chr9-137162734-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376787.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.2008C>A	p.Pro670Thr	missense_variant	14/20	ENST00000371561.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN1	ENST00000371561.8	c.2008C>A	p.Pro670Thr	missense_variant	14/20	1	NM_007327.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1452284 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 721734

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Dec 09, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.;.;D;.;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.8	M;M;.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.2	D;D;D;D;D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.015	D;D;D;D;D;D;D
Sift4G	Uncertain	0.029	D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;.;D;.
Vest4		0.64
MutPred		0.60		Gain of phosphorylation at P670 (P = 0.0675);Gain of phosphorylation at P670 (P = 0.0675);.;.;.;Gain of phosphorylation at P670 (P = 0.0675);.;
MVP		0.76
MPC		3.5
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.83
gMVP		0.97

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: rs1057520055; hg19: chr9-140057186;