9-137139499-C-T

Variant names:

• chr9-137139499-C-T
• rs755880462
• NM_007327.4:c.13C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_007327.4(GRIN1):​c.13C>T​(p.Arg5Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,442,502 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GRIN1 NM_007327.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.20
• Publications: 2 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: G2P, Labcorp Genetics (formerly Invitae), 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: Ambry Genetics, G2P
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN1	NM_007327.4	MANE Select	c.13C>T	p.Arg5Cys	missense	Exon 1 of 20	NP_015566.1	Q05586-1
	GRIN1	NM_001437330.1		c.13C>T	p.Arg5Cys	missense	Exon 1 of 21	NP_001424259.1
	GRIN1	NM_001185090.2		c.13C>T	p.Arg5Cys	missense	Exon 1 of 21	NP_001172019.1	Q05586-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN1	ENST00000371561.8	TSL:1 MANE Select	c.13C>T	p.Arg5Cys	missense	Exon 1 of 20	ENSP00000360616.3	Q05586-1
	GRIN1	ENST00000371553.8	TSL:1	c.13C>T	p.Arg5Cys	missense	Exon 1 of 21	ENSP00000360608.3	Q05586-6
	GRIN1	ENST00000371560.5	TSL:1	c.13C>T	p.Arg5Cys	missense	Exon 1 of 20	ENSP00000360615.3	Q05586-7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000875 AC: 2 AN: 228636 AF XY: 0.0000159

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000976

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1442502 Hom.: 0 Cov.: 32 AF XY: 0.00000419 AC XY: 3 AN XY: 715690

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33164

American (AMR) AF: 0.00 AC: 0 AN: 44056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25862

East Asian (EAS) AF: 0.00 AC: 0 AN: 39166

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85460

European-Finnish (FIN) AF: 0.0000215 AC: 1 AN: 46566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102966

Other (OTH) AF: 0.00 AC: 0 AN: 59608

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00242438), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.00059	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.039
Eigen_PC	Benign	0.0052
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.81	L
PhyloP100		3.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.18
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.025	D
Polyphen		1.0	D
Vest4		0.33
MutPred		0.51		Gain of catalytic residue at L6 (P = 0.0088)
MVP		0.80
MPC		2.3
ClinPred		0.70	D
GERP RS		3.0
PromoterAI		-0.13	Neutral
Varity_R		0.12
gMVP		0.83
Mutation Taster		=68/32	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: rs755880462; hg19: chr9-140033951;