rs201818201

Positions:

• chr9-137156690-A-C
• chr9-137156690-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_007327.4(GRIN1):​c.693A>C​(p.Val231Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000795 in 1,599,020 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00083 (1 hom.)
• Consequence: GRIN1 NM_007327.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.26

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 9-137156690-A-C is Benign according to our data. Variant chr9-137156690-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 385654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137156690-A-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.26 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000512 (78/152328) while in subpopulation SAS AF= 0.00165 (8/4834). AF 95% confidence interval is 0.000823. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIN1	NM_007327.4	c.693A>C	p.Val231Val	synonymous_variant	5/20	ENST00000371561.8	NP_015566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIN1	ENST00000371561.8	c.693A>C	p.Val231Val	synonymous_variant	5/20	1	NM_007327.4	ENSP00000360616.3

Frequencies

GnomAD3 genomes AF: 0.000512 AC: 78 AN: 152210 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000542 AC: 120 AN: 221366 Hom.: 0 AF XY: 0.000574 AC XY: 69 AN XY: 120138

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000216

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000834

Gnomad FIN exome AF: 0.0000546

Gnomad NFE exome AF: 0.000888

Gnomad OTH exome AF: 0.000360

GnomAD4 exome AF: 0.000825 AC: 1194 AN: 1446692 Hom.: 1 Cov.: 34 AF XY: 0.000860 AC XY: 618 AN XY: 718348

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.000185

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.00121

Gnomad4 FIN exome AF: 0.0000397

Gnomad4 NFE exome AF: 0.000952

Gnomad4 OTH exome AF: 0.000368

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152328 Hom.: 0 Cov.: 34 AF XY: 0.000564 AC XY: 42 AN XY: 74492

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00165

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000445 Hom.: 0

Bravo AF: 0.000484

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	GRIN1: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2021	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2016

This alteration is classified as likely 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. -

Intellectual disability, autosomal dominant 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	15
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs201818201; hg19: chr9-140051142;