NM_007327.4:c.1382A>T

Variant names:

• chr9-137161331-A-T
• rs955781126
• NM_007327.4:c.1382A>T
• GRIN1 p.Asp461Val

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+3 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 3 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingPP3_Moderate

The NM_007327.4(GRIN1):c.1382A>T (p.Asp461Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000124 (AC=2) in the gnomAD database across 1,612,346 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000147. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.56). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.D461= (synonymous): Likely_benign (ClinVar VariationId 1572773, 1 star); p.D461G: Uncertain_significance (ClinVar VariationId 521271, 2 stars)

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GRIN1 NM_007327.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.56
• Publications: 3 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: PanelApp Australia, 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: G2P, Ambry Genetics
• developmental and epileptic encephalopathy 101

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• GRIN1-related complex neurodevelopmental disorder

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000147 — borderline rare for AD+AR gene (threshold 0.0001) — PM2 supporting.
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_007327.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	GRIN1 NM_007327.4	MANE Select	c.1382A>T p.Asp461Val	missense	Exon 10 of 20	Prot: NP_015566.1 UniProt:
	GRIN1 NM_001437330.1		c.1445A>T p.Asp482Val	missense	Exon 11 of 21	Prot: NP_001424259.1 UniProt:
	GRIN1 NM_001185090.2		c.1445A>T p.Asp482Val	missense	Exon 11 of 21	Prot: NP_001172019.1 UniProt:

GRIN1 NM_007327.4

MANE Select

HGVSc / HGVSpc.1382A>Tp.Asp461Val

Exon rankExon 10 of 20

missense

Prot: NP_015566.1UniProt: Q05586-1

GRIN1 NM_001437330.1

HGVSc / HGVSpc.1445A>Tp.Asp482Val

Exon rankExon 11 of 21

missense

Prot: NP_001424259.1UniProt: Q05586-5

GRIN1 NM_001185090.2

HGVSc / HGVSpc.1445A>Tp.Asp482Val

Exon rankExon 11 of 21

missense

Prot: NP_001172019.1UniProt: Q05586-6

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	GRIN1 ENST00000371561.8	TSL:1MANE Select	c.1382A>T p.Asp461Val	missense	Exon 10 of 20	Prot: ENSP00000360616.3 UniProt:
	GRIN1 ENST00000371553.8	TSL:1	c.1445A>T p.Asp482Val	missense	Exon 11 of 21	Prot: ENSP00000360608.3 UniProt:
	GRIN1 ENST00000371560.5	TSL:1	c.1445A>T p.Asp482Val	missense	Exon 11 of 20	Prot: ENSP00000360615.3 UniProt:

GRIN1 ENST00000371561.8

TSL:1MANE Select

HGVSc / HGVSpc.1382A>Tp.Asp461Val

Exon rankExon 10 of 20

missense

Prot: ENSP00000360616.3UniProt: Q05586-1

GRIN1 ENST00000371553.8

TSL:1

HGVSc / HGVSpc.1445A>Tp.Asp482Val

Exon rankExon 11 of 21

missense

Prot: ENSP00000360608.3UniProt: Q05586-6

GRIN1 ENST00000371560.5

TSL:1

HGVSc / HGVSpc.1445A>Tp.Asp482Val

Exon rankExon 11 of 20

missense

Prot: ENSP00000360615.3UniProt: Q05586-7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000658	AC:1	Hom:0	AN:151914	Cov:32
GnomAD2 exomes	AF: 0.00000401	AC:1	Hom:	AN:249408	Cov:
GnomAD4 exome	AF: 6.85e-7	AC:1	Hom:0	AN:1460432	Cov:40
GnomAD4 genome	AF: 0.00000658	AC:1	Hom:0	AN:151914	Cov:32
TOPMed (Bravo)	AF: 0.00000756	AC:2	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000262	AC:1	Hom:0	AN:38222	Cov:

Showing 6 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	28
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-11
GPN-Star score	N/A	11
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.45	D
Mutation Taster	N/A	6/94	disease causing
MutationAssessor	Pathogenic	3.7	H
PhyloP100	Pathogenic	8.6
popEVE	Pathogenic	-5.4
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.93
VESM-3B	Benign	-16

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.11	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs955781126;

hg19: chr9-140055783;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar