rs1554770054

chr9-137162195-C-Achr9-137162195-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1 PM1 PM2 PP2 PP5

The NM_007327.4(GRIN1):c.1656C>A(p.Asp552Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GRIN1 NM_007327.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.76

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 Pathogenic. Variant got 10 ACMG points.

• PS1: Transcript NM_007327.4 (GRIN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 487500
• PM1: In a hotspot region, there are 6 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
• PP2: Missense variant where missense usually causes diseases, GRIN1
• PP5: Variant 9-137162195-C-A is Pathogenic according to our data. Variant chr9-137162195-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 487501.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-137162195-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN1	NM_007327.4	c.1656C>A	p.Asp552Glu	missense_variant	12/20	ENST00000371561.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN1	ENST00000371561.8	c.1656C>A	p.Asp552Glu	missense_variant	12/20	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: 1392104 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 687540

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: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, autosomal dominant 8 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 22, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.;.;T;.;.;.
Eigen	Benign	0.052
Eigen_PC	Benign	0.015
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;.;.;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.33	T;T;T;T;T;T;T
Sift4G	Benign	0.45	T;T;T;T;T;T;T
Polyphen		0.98	D;D;.;.;.;D;.
Vest4		0.88
MutPred		0.60		Loss of catalytic residue at D552 (P = 0.0867);Loss of catalytic residue at D552 (P = 0.0867);.;.;.;Loss of catalytic residue at D552 (P = 0.0867);.;
MVP		0.83
MPC		3.1
ClinPred		0.79	D
GERP RS		2.9
Varity_R		0.16
gMVP		0.94

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: rs1554770054; hg19: chr9-140056647;