rs1057520055

Variant names:

• chr9-137162734-C-A
• rs1057520055
• NM_007327.4:c.2008C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-137162734-C-A
• chr9-137162734-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_007327.4(GRIN1):​c.2008C>A​(p.Pro670Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, MODERATE Submitted by: G2P, Ambry Genetics
• developmental and epileptic encephalopathy 101

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 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
• PM2: Very rare variant in population databases, with high coverage
• 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 VariationId is 376787.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007327.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN1	NM_007327.4	MANE Select	c.2008C>A	p.Pro670Thr	missense	Exon 14 of 20	NP_015566.1
	GRIN1	NM_001437330.1		c.2071C>A	p.Pro691Thr	missense	Exon 15 of 21	NP_001424259.1
	GRIN1	NM_001185090.2		c.2071C>A	p.Pro691Thr	missense	Exon 15 of 21	NP_001172019.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN1	ENST00000371561.8	TSL:1 MANE Select	c.2008C>A	p.Pro670Thr	missense	Exon 14 of 20	ENSP00000360616.3
	GRIN1	ENST00000371553.8	TSL:1	c.2071C>A	p.Pro691Thr	missense	Exon 15 of 21	ENSP00000360608.3
	GRIN1	ENST00000371560.5	TSL:1	c.2071C>A	p.Pro691Thr	missense	Exon 15 of 20	ENSP00000360615.3

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

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 43268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25854

East Asian (EAS) AF: 0.00 AC: 0 AN: 39406

South Asian (SAS) AF: 0.00 AC: 0 AN: 85010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108294

Other (OTH) AF: 0.00 AC: 0 AN: 60016

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.7
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.029	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.60		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
Mutation Taster		=17/83	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057520055; hg19: chr9-140057186;