9-137139487-A-G

Variant names:

• chr9-137139487-A-G
• NM_007327.4:c.1A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PVS1_Supporting PM2 BP6_Moderate

The NM_007327.4(GRIN1):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRIN1 NM_007327.4 start_lost
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.66
• 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.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 4 codons. Genomic position: 137139496. Lost 0.004 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 9-137139487-A-G is Benign according to our data. Variant chr9-137139487-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3652142.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN1	NM_007327.4	c.1A>G	p.Met1?	start_lost	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.1A>G	p.Met1?	start_lost	Exon 1 of 20	1	NM_007327.4	ENSP00000360616.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant Benign:1

May 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T;.;.;T;.;.;.
Eigen	Benign	-0.056
Eigen_PC	Benign	-0.029
FATHMM_MKL	Benign	0.031	N
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Benign	-0.65	T
PhyloP100		2.7
PROVEAN	Benign	-0.91	N;N;N;N;N;N;N
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Benign	0.37	T;T;T;T;T;T;T
Polyphen		0.32	B;B;.;.;.;B;.
Vest4		0.65
MutPred		0.99		Loss of phosphorylation at S2 (P = 0.1027);Loss of phosphorylation at S2 (P = 0.1027);Loss of phosphorylation at S2 (P = 0.1027);Loss of phosphorylation at S2 (P = 0.1027);Loss of phosphorylation at S2 (P = 0.1027);Loss of phosphorylation at S2 (P = 0.1027);Loss of phosphorylation at S2 (P = 0.1027);
MVP		0.80
ClinPred		0.99	D
GERP RS		2.9
PromoterAI		-0.034	Neutral
Varity_R		0.85
gMVP		0.88
Mutation Taster		=134/66	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

hg19: chr9-140033939;