9-137140083-T-C

Variant names:

• chr9-137140083-T-C
• rs2301364
• NM_007327.4:c.258+339T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007327.4(GRIN1):​c.258+339T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 152,132 control chromosomes in the GnomAD database, including 1,998 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (1998 hom., cov: 33)
• Consequence: GRIN1 NM_007327.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.277
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

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.258+339T>C		intron	N/A	NP_015566.1
	GRIN1	NM_001437330.1		c.258+339T>C		intron	N/A	NP_001424259.1
	GRIN1	NM_001185090.2		c.258+339T>C		intron	N/A	NP_001172019.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN1	ENST00000371561.8	TSL:1 MANE Select	c.258+339T>C		intron	N/A	ENSP00000360616.3
	GRIN1	ENST00000371553.8	TSL:1	c.258+339T>C		intron	N/A	ENSP00000360608.3
	GRIN1	ENST00000371560.5	TSL:1	c.258+339T>C		intron	N/A	ENSP00000360615.3

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23113 AN: 152012 Hom.: 1986 Cov.: 33

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.0969

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.150

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.163

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.152 AC: 23165 AN: 152132 Hom.: 1998 Cov.: 33 AF XY: 0.158 AC XY: 11737 AN XY: 74394

African (AFR) AF: 0.175 AC: 7273 AN: 41494

American (AMR) AF: 0.185 AC: 2826 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0969 AC: 336 AN: 3468

East Asian (EAS) AF: 0.233 AC: 1200 AN: 5158

South Asian (SAS) AF: 0.313 AC: 1511 AN: 4822

European-Finnish (FIN) AF: 0.139 AC: 1474 AN: 10594

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8054 AN: 67988

Other (OTH) AF: 0.167 AC: 354 AN: 2114

Alfa AF: 0.117 Hom.: 469

Bravo AF: 0.153

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.7
DANN	Benign	0.71
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

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: rs2301364; hg19: chr9-140034535; COSMIC: COSV59301627;