chr9-137158422-G-C

Variant names:

• chr9-137158422-G-C
• rs140672142
• NM_007327.4:c.1012G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The NM_007327.4(GRIN1):​c.1012G>C​(p.Val338Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V338M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRIN1 NM_007327.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.35
• 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

LOC105376328 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36103445).
• BP6: Variant 9-137158422-G-C is Benign according to our data. Variant chr9-137158422-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1655991.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.1012G>C	p.Val338Leu	missense	Exon 7 of 20	NP_015566.1
	GRIN1	NM_001437330.1		c.1075G>C	p.Val359Leu	missense	Exon 8 of 21	NP_001424259.1
	GRIN1	NM_001185090.2		c.1075G>C	p.Val359Leu	missense	Exon 8 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.1012G>C	p.Val338Leu	missense	Exon 7 of 20	ENSP00000360616.3
	GRIN1	ENST00000371553.8	TSL:1	c.1075G>C	p.Val359Leu	missense	Exon 8 of 21	ENSP00000360608.3
	GRIN1	ENST00000371560.5	TSL:1	c.1075G>C	p.Val359Leu	missense	Exon 8 of 20	ENSP00000360615.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant Benign:1

Jan 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.4
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.18
Sift	Benign	0.47	T
Sift4G	Benign	0.10	T
Polyphen		0.064	B
Vest4		0.35
MutPred		0.80		Loss of sheet (P = 0.0817)
MVP		0.77
MPC		1.3
ClinPred		0.54	D
GERP RS		4.0
Varity_R		0.32
gMVP		0.83
Mutation Taster		=76/24	polymorphism

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: rs140672142; hg19: chr9-140052874;