rs9373491

Positions:

• chr6-146434706-C-A
• chr6-146434706-C-G
• chr6-146434706-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001278064.2(GRM1):​c.3495C>A​(p.Pro1165Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 1,602,804 control chromosomes in the GnomAD database, including 226,687 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24251 hom., cov: 33)
  • Exomes 𝑓: 0.53 (202436 hom.)
• Consequence: GRM1 NM_001278064.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -7.05

Genes affected

GRM1 (HGNC:4593): (glutamate metabotropic receptor 1) This gene encodes a metabotropic glutamate receptor that functions by activating phospholipase C. L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The canonical alpha isoform of the encoded protein is a disulfide-linked homodimer whose activity is mediated by a G-protein-coupled phosphatidylinositol-calcium second messenger system. This gene may be associated with many disease states, including schizophrenia, bipolar disorder, depression, and breast cancer. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 6-146434706-C-A is Benign according to our data. Variant chr6-146434706-C-A is described in ClinVar as [Benign]. Clinvar id is 129213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-146434706-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-7.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM1	NM_001278064.2	c.3495C>A	p.Pro1165Pro	synonymous_variant	8/8	ENST00000282753.6	NP_001264993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRM1	ENST00000282753.6	c.3495C>A	p.Pro1165Pro	synonymous_variant	8/8	1	NM_001278064.2	ENSP00000282753.1

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84959 AN: 152006 Hom.: 24226 Cov.: 33

Gnomad AFR AF: 0.673

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.603

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.562

GnomAD3 exomes AF: 0.520 AC: 124677 AN: 239870 Hom.: 33324 AF XY: 0.524 AC XY: 68830 AN XY: 131308

Gnomad AFR exome AF: 0.678

Gnomad AMR exome AF: 0.396

Gnomad ASJ exome AF: 0.573

Gnomad EAS exome AF: 0.515

Gnomad SAS exome AF: 0.600

Gnomad FIN exome AF: 0.447

Gnomad NFE exome AF: 0.519

Gnomad OTH exome AF: 0.526

GnomAD4 exome AF: 0.526 AC: 762612 AN: 1450680 Hom.: 202436 Cov.: 48 AF XY: 0.528 AC XY: 381525 AN XY: 722168

Gnomad4 AFR exome AF: 0.676

Gnomad4 AMR exome AF: 0.405

Gnomad4 ASJ exome AF: 0.568

Gnomad4 EAS exome AF: 0.496

Gnomad4 SAS exome AF: 0.600

Gnomad4 FIN exome AF: 0.447

Gnomad4 NFE exome AF: 0.522

Gnomad4 OTH exome AF: 0.541

GnomAD4 genome AF: 0.559 AC: 85025 AN: 152124 Hom.: 24251 Cov.: 33 AF XY: 0.555 AC XY: 41276 AN XY: 74382

Gnomad4 AFR AF: 0.673

Gnomad4 AMR AF: 0.491

Gnomad4 ASJ AF: 0.565

Gnomad4 EAS AF: 0.521

Gnomad4 SAS AF: 0.604

Gnomad4 FIN AF: 0.447

Gnomad4 NFE AF: 0.522

Gnomad4 OTH AF: 0.566

Alfa AF: 0.501 Hom.: 5145

Bravo AF: 0.563

Asia WGS AF: 0.579 AC: 2014 AN: 3478

EpiCase AF: 0.535

EpiControl AF: 0.536

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 15, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

not specified Benign:2

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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autosomal recessive spinocerebellar ataxia 13 Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Spinocerebellar ataxia 44 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	-0.65
CADD	Benign	0.31
DANN	Benign	0.90

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: rs9373491; hg19: chr6-146755842; COSMIC: COSV51124985;