chr9-137162182-G-T

Variant names:

• chr9-137162182-G-T
• rs1554770044
• NM_007327.4:c.1643G>T
• GRIN1 p.Arg548Leu

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 (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO7_Supporting

The NM_007327.4(GRIN1):c.1643G>T (p.Arg548Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The gene GRIN1 is a known oncogene (CancerMine: 2 oncogene citations). The variant has a gnomAD grpmax filtering allele frequency (95% CI) of 0.000000718, indicating it is observed in the general population. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.36). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R548Q: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 521298) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R548G: Uncertain_significance (ClinVar VariationId 1512865, 1 star)

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: GRIN1 NM_007327.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.36
• 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 ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000001, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 9 pathogenic, 0 benign (OR vs. background: 95.0); Variant does not impact splicing — splice-hotspot path not applicable

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.1643G>T p.Arg548Leu	missense	Exon 12 of 20	Prot: NP_015566.1 UniProt:
	GRIN1 NM_001437330.1		c.1706G>T p.Arg569Leu	missense	Exon 13 of 21	Prot: NP_001424259.1 UniProt:
	GRIN1 NM_001185090.2		c.1706G>T p.Arg569Leu	missense	Exon 13 of 21	Prot: NP_001172019.1 UniProt:

GRIN1 NM_007327.4

MANE Select

HGVSc / HGVSpc.1643G>Tp.Arg548Leu

Exon rankExon 12 of 20

missense

Prot: NP_015566.1UniProt: Q05586-1

GRIN1 NM_001437330.1

HGVSc / HGVSpc.1706G>Tp.Arg569Leu

Exon rankExon 13 of 21

missense

Prot: NP_001424259.1UniProt: Q05586-5

GRIN1 NM_001185090.2

HGVSc / HGVSpc.1706G>Tp.Arg569Leu

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.1643G>T p.Arg548Leu	missense	Exon 12 of 20	Prot: ENSP00000360616.3 UniProt:
	GRIN1 ENST00000371553.8	TSL:1	c.1706G>T p.Arg569Leu	missense	Exon 13 of 21	Prot: ENSP00000360608.3 UniProt:
	GRIN1 ENST00000371560.5	TSL:1	c.1706G>T p.Arg569Leu	missense	Exon 13 of 20	Prot: ENSP00000360615.3 UniProt:

GRIN1 ENST00000371561.8

TSL:1MANE Select

HGVSc / HGVSpc.1643G>Tp.Arg548Leu

Exon rankExon 12 of 20

missense

Prot: ENSP00000360616.3UniProt: Q05586-1

GRIN1 ENST00000371553.8

TSL:1

HGVSc / HGVSpc.1706G>Tp.Arg569Leu

Exon rankExon 13 of 21

missense

Prot: ENSP00000360608.3UniProt: Q05586-6

GRIN1 ENST00000371560.5

TSL:1

HGVSc / HGVSpc.1706G>Tp.Arg569Leu

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 Warning	AF: 7.18e-7	AC:1	Hom:0	AN:1391986	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	26
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.97	D
FuncVEP CTI	Pathogenic	0.98
GPN-Star LLR	N/A	-11
GPN-Star score	N/A	11
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	-0.21	T
Mutation Taster	N/A	39/61	disease causing
MutationAssessor	Benign	1.7	L
PhyloP100	Uncertain	7.4
popEVE	Uncertain	-4.7
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.52
Sift	Benign	0.050	D
Sift4G	Benign	0.28	T
Varity_R	N/A	0.55
VESM-3B	Benign	-12

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
DS_AG_spliceai	Uncertain	0.31	Position offset: 26
Pangolin (max)	Benign	0.050
SpliceAI score (max)	Uncertain	0.31	Details are displayed if max score is > 0.2

Showing 3 of 3 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: rs1554770044;

hg19: chr9-140056634;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar