rs10747050

Positions:

• chr9-137161424-G-A

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 129179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137161424-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.965 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN1	NM_007327.4	c.1467+8G>A		splice_region_variant, intron_variant		ENST00000371561.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN1	ENST00000371561.8	c.1467+8G>A		splice_region_variant, intron_variant		1	NM_007327.4

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

GnomAD3 exomes AF: 0.937 AC: 229187 AN: 244588 Hom.: 107683 AF XY: 0.931 AC XY: 123679 AN XY: 132878

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 SAS exome AF: 0.826

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

Gnomad4 AFR exome AF: 0.974

Gnomad4 AMR exome AF: 0.964

Gnomad4 ASJ exome AF: 0.887

Gnomad4 EAS exome AF: 0.990

Gnomad4 SAS exome AF: 0.832

Gnomad4 FIN exome AF: 0.983

Gnomad4 NFE exome AF: 0.936

Gnomad4 OTH exome AF: 0.928

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

Gnomad4 AFR AF: 0.973

Gnomad4 AMR AF: 0.946

Gnomad4 ASJ AF: 0.902

Gnomad4 EAS AF: 0.981

Gnomad4 SAS AF: 0.831

Gnomad4 FIN AF: 0.979

Gnomad4 NFE AF: 0.939

Gnomad4 OTH AF: 0.940

Alfa AF: 0.940 Hom.: 88888

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

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2016	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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Intellectual disability, autosomal dominant 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2016

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.0
DANN	Benign	0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs10747050; hg19: chr9-140055876;