rs9373491

Variant names:

• chr6-146434706-C-A
• rs9373491
• NM_001278064.2:c.3495C>A

Your query was ambiguous. Multiple possible variants found:

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

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.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
• 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=-0.65).
• BP6: Variant 6-146434706-C-A is Benign according to our data. Variant chr6-146434706-C-A is described in ClinVar as Benign. ClinVar VariationId is 129213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.3495C>A	p.Pro1165Pro	synonymous	Exon 8 of 8	NP_001264993.1	Q13255-1
	GRM1	NM_001278067.1		c.*733C>A		3_prime_UTR	Exon 8 of 8	NP_001264996.1	Q59HC2
	GRM1	NM_001278065.2		c.*859C>A		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.3495C>A	p.Pro1165Pro	synonymous	Exon 8 of 8	ENSP00000282753.1	Q13255-1
	GRM1	ENST00000355289.8	TSL:1	c.*733C>A		3_prime_UTR	Exon 8 of 8	ENSP00000347437.4	Q13255-3
	GRM1	ENST00000492807.6	TSL:1	c.*859C>A		3_prime_UTR	Exon 10 of 10	ENSP00000424095.1	Q13255-2

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

GnomAD2 exomes AF: 0.520 AC: 124677 AN: 239870 AF XY: 0.524

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 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

African (AFR) AF: 0.676 AC: 22641 AN: 33468

American (AMR) AF: 0.405 AC: 18097 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.568 AC: 14839 AN: 26130

East Asian (EAS) AF: 0.496 AC: 19699 AN: 39694

South Asian (SAS) AF: 0.600 AC: 51715 AN: 86252

European-Finnish (FIN) AF: 0.447 AC: 19058 AN: 42644

Middle Eastern (MID) AF: 0.570 AC: 3284 AN: 5766

European-Non Finnish (NFE) AF: 0.522 AC: 580619 AN: 1111686

Other (OTH) AF: 0.541 AC: 32660 AN: 60322

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

African (AFR) AF: 0.673 AC: 27929 AN: 41494

American (AMR) AF: 0.491 AC: 7515 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1961 AN: 3472

East Asian (EAS) AF: 0.521 AC: 2684 AN: 5154

South Asian (SAS) AF: 0.604 AC: 2915 AN: 4826

European-Finnish (FIN) AF: 0.447 AC: 4737 AN: 10594

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.522 AC: 35515 AN: 67972

Other (OTH) AF: 0.566 AC: 1196 AN: 2114

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

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	-0.65
CADD	Benign	0.31
DANN	Benign	0.90
PhyloP100		-7.1
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: rs9373491; hg19: chr6-146755842; COSMIC: COSV51124985;