rs6923864

Variant names:

• chr6-146434379-T-G
• rs6923864
• NM_001278064.2:c.3168T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001278064.2(GRM1):​c.3168T>G​(p.Gly1056Gly) 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 NM_001278064.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.00
• Publications: 17 publications found

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]

GRM1 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia 44

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal recessive spinocerebellar ataxia 13

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 129211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278064.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM1	NM_001278064.2	MANE Select	c.3168T>G	p.Gly1056Gly	synonymous	Exon 8 of 8	NP_001264993.1	Q13255-1
	GRM1	NM_001278067.1		c.*406T>G		3_prime_UTR	Exon 8 of 8	NP_001264996.1	Q59HC2
	GRM1	NM_001278065.2		c.*532T>G		3_prime_UTR	Exon 10 of 10	NP_001264994.1	Q13255-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM1	ENST00000282753.6	TSL:1 MANE Select	c.3168T>G	p.Gly1056Gly	synonymous	Exon 8 of 8	ENSP00000282753.1	Q13255-1
	GRM1	ENST00000355289.8	TSL:1	c.*406T>G		3_prime_UTR	Exon 8 of 8	ENSP00000347437.4	Q13255-3
	GRM1	ENST00000492807.6	TSL:1	c.*532T>G		3_prime_UTR	Exon 10 of 10	ENSP00000424095.1	Q13255-2

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

GnomAD2 exomes AF: 0.565 AC: 137647 AN: 243838 AF XY: 0.567

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 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

African (AFR) AF: 0.902 AC: 30179 AN: 33468

American (AMR) AF: 0.436 AC: 19476 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 15863 AN: 26088

East Asian (EAS) AF: 0.567 AC: 22513 AN: 39678

South Asian (SAS) AF: 0.648 AC: 55833 AN: 86188

European-Finnish (FIN) AF: 0.471 AC: 25004 AN: 53066

Middle Eastern (MID) AF: 0.622 AC: 3586 AN: 5766

European-Non Finnish (NFE) AF: 0.551 AC: 612432 AN: 1111300

Other (OTH) AF: 0.590 AC: 35585 AN: 60336

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

African (AFR) AF: 0.887 AC: 36858 AN: 41550

American (AMR) AF: 0.541 AC: 8273 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 2103 AN: 3472

East Asian (EAS) AF: 0.592 AC: 3045 AN: 5146

South Asian (SAS) AF: 0.657 AC: 3164 AN: 4818

European-Finnish (FIN) AF: 0.471 AC: 4983 AN: 10590

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.551 AC: 37424 AN: 67972

Other (OTH) AF: 0.633 AC: 1336 AN: 2112

Alfa AF: 0.603 Hom.: 12533

Bravo AF: 0.654

Asia WGS AF: 0.639 AC: 2221 AN: 3476

EpiCase AF: 0.563

EpiControl AF: 0.565

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Autosomal recessive spinocerebellar ataxia 13 (2)
-	-	2	not specified (2)
-	-	1	Spinocerebellar ataxia 44 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.0
DANN	Benign	0.75
PhyloP100		2.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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