rs6923864

Positions:

• chr6-146434379-T-G

Variant summary

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

The ENST00000282753.6(GRM1):​c.3168T>G​(p.Gly1056=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 1,612,734 control chromosomes in the GnomAD database, including 267,608 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (33359 hom., cov: 33)
  • Exomes 𝑓: 0.56 (234249 hom.)
• Consequence: GRM1 ENST00000282753.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.00

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=-0.59).
• BP6: Variant 6-146434379-T-G is Benign according to our data. Variant chr6-146434379-T-G is described in ClinVar as [Benign]. Clinvar id is 129211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-146434379-T-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.879 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM1	NM_001278064.2	c.3168T>G	p.Gly1056=	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.3168T>G	p.Gly1056=	synonymous_variant	8/8	1	NM_001278064.2	ENSP00000282753	P1

Frequencies

GnomAD3 genomes AF: 0.643 AC: 97723 AN: 152046 Hom.: 33300 Cov.: 33

Gnomad AFR AF: 0.887

Gnomad AMI AF: 0.533

Gnomad AMR AF: 0.541

Gnomad ASJ AF: 0.606

Gnomad EAS AF: 0.591

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.471

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.551

Gnomad OTH AF: 0.631

GnomAD3 exomes AF: 0.565 AC: 137647 AN: 243838 Hom.: 40488 AF XY: 0.567 AC XY: 75472 AN XY: 133090

Gnomad AFR exome AF: 0.897

Gnomad AMR exome AF: 0.427

Gnomad ASJ exome AF: 0.615

Gnomad EAS exome AF: 0.589

Gnomad SAS exome AF: 0.647

Gnomad FIN exome AF: 0.467

Gnomad NFE exome AF: 0.550

Gnomad OTH exome AF: 0.564

GnomAD4 exome AF: 0.562 AC: 820471 AN: 1460570 Hom.: 234249 Cov.: 59 AF XY: 0.564 AC XY: 409704 AN XY: 726504

Gnomad4 AFR exome AF: 0.902

Gnomad4 AMR exome AF: 0.436

Gnomad4 ASJ exome AF: 0.608

Gnomad4 EAS exome AF: 0.567

Gnomad4 SAS exome AF: 0.648

Gnomad4 FIN exome AF: 0.471

Gnomad4 NFE exome AF: 0.551

Gnomad4 OTH exome AF: 0.590

GnomAD4 genome AF: 0.643 AC: 97839 AN: 152164 Hom.: 33359 Cov.: 33 AF XY: 0.638 AC XY: 47435 AN XY: 74372

Gnomad4 AFR AF: 0.887

Gnomad4 AMR AF: 0.541

Gnomad4 ASJ AF: 0.606

Gnomad4 EAS AF: 0.592

Gnomad4 SAS AF: 0.657

Gnomad4 FIN AF: 0.471

Gnomad4 NFE AF: 0.551

Gnomad4 OTH AF: 0.633

Alfa AF: 0.600 Hom.: 12224

Bravo AF: 0.654

Asia WGS AF: 0.639 AC: 2221 AN: 3476

EpiCase AF: 0.563

EpiControl AF: 0.565

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

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	-0.59
CADD	Benign	9.0
DANN	Benign	0.75

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: rs6923864; hg19: chr6-146755515; COSMIC: COSV51118480;