rs139637382

chr9-137161969-C-T

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.1513C>T(p.Leu505=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000501 in 1,565,884 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00050 (3 hom.)
• Consequence: GRIN1 NM_007327.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.31

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 9-137161969-C-T is Benign according to our data. Variant chr9-137161969-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 382146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137161969-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.31 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000558 (85/152300) while in subpopulation AMR AF= 0.00105 (16/15308). AF 95% confidence interval is 0.000655. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN1	NM_007327.4	c.1513C>T	p.Leu505=	synonymous_variant	11/20	ENST00000371561.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN1	ENST00000371561.8	c.1513C>T	p.Leu505=	synonymous_variant	11/20	1	NM_007327.4

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 152182 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000823 AC: 146 AN: 177466 Hom.: 0 AF XY: 0.000793 AC XY: 75 AN XY: 94552

Gnomad AFR exome AF: 0.000390

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00102

Gnomad EAS exome AF: 0.0000752

Gnomad SAS exome AF: 0.000292

Gnomad FIN exome AF: 0.000313

Gnomad NFE exome AF: 0.000546

Gnomad OTH exome AF: 0.00312

GnomAD4 exome AF: 0.000495 AC: 700 AN: 1413584 Hom.: 3 Cov.: 34 AF XY: 0.000505 AC XY: 353 AN XY: 698796

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.00211

Gnomad4 ASJ exome AF: 0.00102

Gnomad4 EAS exome AF: 0.0000271

Gnomad4 SAS exome AF: 0.000261

Gnomad4 FIN exome AF: 0.000348

Gnomad4 NFE exome AF: 0.000359

Gnomad4 OTH exome AF: 0.00102

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152300 Hom.: 0 Cov.: 31 AF XY: 0.000537 AC XY: 40 AN XY: 74462

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000900 Hom.: 0

Bravo AF: 0.000706

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	GRIN1: BP4, BP7 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 07, 2017

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2015

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

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	13
Dann	Uncertain	0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs139637382; hg19: chr9-140056421;