9-137139491-G-T

Variant names:

• chr9-137139491-G-T
• rs1832047745
• NM_007327.4:c.5G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007327.4(GRIN1):​c.5G>T​(p.Ser2Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,437,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: GRIN1 NM_007327.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.93
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3879274).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN1	NM_007327.4	c.5G>T	p.Ser2Ile	missense_variant	Exon 1 of 20	ENST00000371561.8	NP_015566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN1	ENST00000371561.8	c.5G>T	p.Ser2Ile	missense_variant	Exon 1 of 20	1	NM_007327.4	ENSP00000360616.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000348 AC: 5 AN: 1437850 Hom.: 0 Cov.: 32 AF XY: 0.00000561 AC XY: 4 AN XY: 712742

African (AFR) AF: 0.00 AC: 0 AN: 33074

American (AMR) AF: 0.00 AC: 0 AN: 43806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25766

East Asian (EAS) AF: 0.00 AC: 0 AN: 39024

South Asian (SAS) AF: 0.00 AC: 0 AN: 85238

European-Finnish (FIN) AF: 0.0000220 AC: 1 AN: 45452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5588

European-Non Finnish (NFE) AF: 0.00000363 AC: 4 AN: 1100540

Other (OTH) AF: 0.00 AC: 0 AN: 59362

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T;.;.;T;.;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.099
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N;N;N;.;N;N;N
PhyloP100		2.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N
REVEL	Benign	0.077
Sift	Uncertain	0.0030	D;D;D;D;D;D;D
Sift4G	Benign	0.063	T;T;T;T;T;T;T
Polyphen		0.12	B;B;.;.;.;B;.
Vest4		0.33
MutPred		0.33		Gain of stability (P = 0.0061);Gain of stability (P = 0.0061);Gain of stability (P = 0.0061);Gain of stability (P = 0.0061);Gain of stability (P = 0.0061);Gain of stability (P = 0.0061);Gain of stability (P = 0.0061);
MVP		0.53
MPC		1.5
ClinPred		0.52	D
GERP RS		3.0
PromoterAI		0.10	Neutral
Varity_R		0.23
gMVP		0.92
Mutation Taster		=95/5	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: rs1832047745; hg19: chr9-140033943; COSMIC: COSV108126870;