9-137162186-C-G

Variant names:

• chr9-137162186-C-G
• NM_007327.4:c.1647C>G
• GRIN1 p.Ser549Arg

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+13 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 13 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPM1PM2PP3

The NM_007327.4(GRIN1):c.1647C>G (p.Ser549Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. 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.S549= (synonymous): Likely_benign (ClinVar VariationId 539842, 2 stars)

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRIN1 NM_007327.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26
• 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: 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: Pathogenic. The variant received 13 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 2 stars).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 11 pathogenic, 0 benign (OR vs. background: 115.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).

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.1647C>G p.Ser549Arg	missense	Exon 12 of 20	Prot: NP_015566.1 UniProt:
	GRIN1 NM_001437330.1		c.1710C>G p.Ser570Arg	missense	Exon 13 of 21	Prot: NP_001424259.1 UniProt:
	GRIN1 NM_001185090.2		c.1710C>G p.Ser570Arg	missense	Exon 13 of 21	Prot: NP_001172019.1 UniProt:

GRIN1 NM_007327.4

MANE Select

HGVSc / HGVSpc.1647C>Gp.Ser549Arg

Exon rankExon 12 of 20

missense

Prot: NP_015566.1UniProt: Q05586-1

GRIN1 NM_001437330.1

HGVSc / HGVSpc.1710C>Gp.Ser570Arg

Exon rankExon 13 of 21

missense

Prot: NP_001424259.1UniProt: Q05586-5

GRIN1 NM_001185090.2

HGVSc / HGVSpc.1710C>Gp.Ser570Arg

Exon rankExon 13 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.1647C>G p.Ser549Arg	missense	Exon 12 of 20	Prot: ENSP00000360616.3 UniProt:
	GRIN1 ENST00000371553.8	TSL:1	c.1710C>G p.Ser570Arg	missense	Exon 13 of 21	Prot: ENSP00000360608.3 UniProt:
	GRIN1 ENST00000371560.5	TSL:1	c.1710C>G p.Ser570Arg	missense	Exon 13 of 20	Prot: ENSP00000360615.3 UniProt:

GRIN1 ENST00000371561.8

TSL:1MANE Select

HGVSc / HGVSpc.1647C>Gp.Ser549Arg

Exon rankExon 12 of 20

missense

Prot: ENSP00000360616.3UniProt: Q05586-1

GRIN1 ENST00000371553.8

TSL:1

HGVSc / HGVSpc.1710C>Gp.Ser570Arg

Exon rankExon 13 of 21

missense

Prot: ENSP00000360608.3UniProt: Q05586-6

GRIN1 ENST00000371560.5

TSL:1

HGVSc / HGVSpc.1710C>Gp.Ser570Arg

Exon rankExon 13 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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	27
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.83	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-9.4
GPN-Star score	N/A	9.4
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	-0.19	T
Mutation Taster	N/A	13/87	disease causing
MutationAssessor	Uncertain	2.8	M
PhyloP100	Benign	1.3
popEVE	Uncertain	-4.8
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.0030	D
Varity_R	N/A	0.74
VESM-3B	Benign	-13

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	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

hg19: chr9-140056638;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar