9-137161424-G-A

Variant names:

• chr9-137161424-G-A
• rs10747050
• NM_007327.4:c.1467+8G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007327.4(GRIN1):​c.1467+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.935 in 1,608,884 control chromosomes in the GnomAD database, including 703,780 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (68030 hom., cov: 24)
  • Exomes 𝑓: 0.93 (635750 hom.)
• Consequence: GRIN1 NM_007327.4 splice_region, intron
• Scores: Splicing: ADA: 0.001443
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.32
• Publications: 15 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 9-137161424-G-A is Benign according to our data. Variant chr9-137161424-G-A is described in ClinVar as Benign. ClinVar VariationId is 129179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.965 is higher than 0.05.

Variant Effect in Transcripts

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

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN1	NM_007327.4	MANE Select	c.1467+8G>A		splice_region intron	N/A	NP_015566.1
	GRIN1	NM_001437330.1		c.1530+8G>A		splice_region intron	N/A	NP_001424259.1
	GRIN1	NM_001185090.2		c.1530+8G>A		splice_region intron	N/A	NP_001172019.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN1	ENST00000371561.8	TSL:1 MANE Select	c.1467+8G>A		splice_region intron	N/A	ENSP00000360616.3
	GRIN1	ENST00000371553.8	TSL:1	c.1530+8G>A		splice_region intron	N/A	ENSP00000360608.3
	GRIN1	ENST00000371560.5	TSL:1	c.1530+8G>A		splice_region intron	N/A	ENSP00000360615.3

Frequencies

GnomAD3 genomes AF: 0.949 AC: 143114 AN: 150776 Hom.: 67981 Cov.: 24

Gnomad AFR AF: 0.973

Gnomad AMI AF: 0.977

Gnomad AMR AF: 0.946

Gnomad ASJ AF: 0.902

Gnomad EAS AF: 0.982

Gnomad SAS AF: 0.831

Gnomad FIN AF: 0.979

Gnomad MID AF: 0.920

Gnomad NFE AF: 0.939

Gnomad OTH AF: 0.941

GnomAD2 exomes AF: 0.937 AC: 229187 AN: 244588 AF XY: 0.931

Gnomad AFR exome AF: 0.975

Gnomad AMR exome AF: 0.965

Gnomad ASJ exome AF: 0.892

Gnomad EAS exome AF: 0.983

Gnomad FIN exome AF: 0.985

Gnomad NFE exome AF: 0.941

Gnomad OTH exome AF: 0.930

GnomAD4 exome AF: 0.933 AC: 1360578 AN: 1458000 Hom.: 635750 Cov.: 45 AF XY: 0.930 AC XY: 674236 AN XY: 725108

African (AFR) AF: 0.974 AC: 32558 AN: 33414

American (AMR) AF: 0.964 AC: 42823 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.887 AC: 23073 AN: 26014

East Asian (EAS) AF: 0.990 AC: 39209 AN: 39606

South Asian (SAS) AF: 0.832 AC: 71536 AN: 85974

European-Finnish (FIN) AF: 0.983 AC: 51075 AN: 51954

Middle Eastern (MID) AF: 0.887 AC: 5095 AN: 5744

European-Non Finnish (NFE) AF: 0.936 AC: 1039276 AN: 1110602

Other (OTH) AF: 0.928 AC: 55933 AN: 60254

GnomAD4 genome AF: 0.949 AC: 143218 AN: 150884 Hom.: 68030 Cov.: 24 AF XY: 0.948 AC XY: 69837 AN XY: 73632

African (AFR) AF: 0.973 AC: 39796 AN: 40912

American (AMR) AF: 0.946 AC: 14371 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.902 AC: 3128 AN: 3466

East Asian (EAS) AF: 0.981 AC: 4983 AN: 5078

South Asian (SAS) AF: 0.831 AC: 3920 AN: 4716

European-Finnish (FIN) AF: 0.979 AC: 10214 AN: 10434

Middle Eastern (MID) AF: 0.914 AC: 265 AN: 290

European-Non Finnish (NFE) AF: 0.939 AC: 63689 AN: 67798

Other (OTH) AF: 0.940 AC: 1967 AN: 2092

Alfa AF: 0.941 Hom.: 114220

Bravo AF: 0.952

Asia WGS AF: 0.881 AC: 3050 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 05, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 99% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 92. Only high quality variants are reported.

Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Inborn genetic diseases Benign:1

May 31, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.0
DANN	Benign	0.89
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0014
dbscSNV1_RF	Benign	0.022
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: rs10747050; hg19: chr9-140055876;