rs75783429

chr9-137162004-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007327.4(GRIN1):c.1548G>A(p.Pro516=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0035 in 1,557,628 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (16 hom., cov: 31)
  • Exomes 𝑓: 0.0032 (91 hom.)
• Consequence: GRIN1 NM_007327.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.64

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=-0.64).
• BP6: Variant 9-137162004-G-A is Benign according to our data. Variant chr9-137162004-G-A is described in ClinVar as [Benign]. Clinvar id is 383643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137162004-G-A is described in Lovd as [Likely_benign]. Variant chr9-137162004-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00626 (952/152072) while in subpopulation EAS AF= 0.0409 (211/5158). AF 95% confidence interval is 0.0364. There are 16 homozygotes in gnomad4. There are 455 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN1	NM_007327.4	c.1548G>A	p.Pro516=	synonymous_variant	11/20	ENST00000371561.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN1	ENST00000371561.8	c.1548G>A	p.Pro516=	synonymous_variant	11/20	1	NM_007327.4

Frequencies

GnomAD3 genomes AF: 0.00619 AC: 940 AN: 151960 Hom.: 15 Cov.: 31

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0406

Gnomad SAS AF: 0.0273

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00811 AC: 1339 AN: 165146 Hom.: 34 AF XY: 0.00879 AC XY: 770 AN XY: 87592

Gnomad AFR exome AF: 0.0141

Gnomad AMR exome AF: 0.00140

Gnomad ASJ exome AF: 0.00151

Gnomad EAS exome AF: 0.0407

Gnomad SAS exome AF: 0.0251

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000852

Gnomad OTH exome AF: 0.00393

GnomAD4 exome AF: 0.00321 AC: 4507 AN: 1405556 Hom.: 91 Cov.: 34 AF XY: 0.00373 AC XY: 2590 AN XY: 694080

Gnomad4 AFR exome AF: 0.0140

Gnomad4 AMR exome AF: 0.00142

Gnomad4 ASJ exome AF: 0.00143

Gnomad4 EAS exome AF: 0.0338

Gnomad4 SAS exome AF: 0.0251

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000338

Gnomad4 OTH exome AF: 0.00596

GnomAD4 genome AF: 0.00626 AC: 952 AN: 152072 Hom.: 16 Cov.: 31 AF XY: 0.00612 AC XY: 455 AN XY: 74322

Gnomad4 AFR AF: 0.0124

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.0409

Gnomad4 SAS AF: 0.0274

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00296 Hom.: 1

Bravo AF: 0.00706

Asia WGS AF: 0.0560 AC: 195 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 19, 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. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 05, 2019

- -

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	-0.64
Cadd	Benign	4.8
Dann	Benign	0.93

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: rs75783429; hg19: chr9-140056456;