6-146434424-T-G

Variant names:

• chr6-146434424-T-G
• rs1047006
• NM_001278064.2:c.3213T>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.3213T>G​(p.Pro1071Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 1,613,082 control chromosomes in the GnomAD database, including 107,186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1071P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.28 (7396 hom., cov: 34)
  • Exomes 𝑓: 0.36 (99790 hom.)
• Consequence: GRM1 NM_001278064.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.40
• Publications: 13 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=-0.92).
• BP6: Variant 6-146434424-T-G is Benign according to our data. Variant chr6-146434424-T-G is described in ClinVar as Benign. ClinVar VariationId is 129212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.385 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.3213T>G	p.Pro1071Pro	synonymous	Exon 8 of 8	NP_001264993.1	Q13255-1
	GRM1	NM_001278067.1		c.*451T>G		3_prime_UTR	Exon 8 of 8	NP_001264996.1	Q59HC2
	GRM1	NM_001278065.2		c.*577T>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.3213T>G	p.Pro1071Pro	synonymous	Exon 8 of 8	ENSP00000282753.1	Q13255-1
	GRM1	ENST00000355289.8	TSL:1	c.*451T>G		3_prime_UTR	Exon 8 of 8	ENSP00000347437.4	Q13255-3
	GRM1	ENST00000492807.6	TSL:1	c.*577T>G		3_prime_UTR	Exon 10 of 10	ENSP00000424095.1	Q13255-2

Frequencies

GnomAD3 genomes AF: 0.284 AC: 43158 AN: 152002 Hom.: 7392 Cov.: 34

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.0830

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.389

Gnomad OTH AF: 0.304

GnomAD2 exomes AF: 0.309 AC: 75743 AN: 245168 AF XY: 0.317

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.244

Gnomad ASJ exome AF: 0.399

Gnomad EAS exome AF: 0.0840

Gnomad FIN exome AF: 0.349

Gnomad NFE exome AF: 0.384

Gnomad OTH exome AF: 0.351

GnomAD4 exome AF: 0.361 AC: 527670 AN: 1460964 Hom.: 99790 Cov.: 54 AF XY: 0.361 AC XY: 262053 AN XY: 726760

African (AFR) AF: 0.0971 AC: 3251 AN: 33472

American (AMR) AF: 0.250 AC: 11171 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 10413 AN: 26106

East Asian (EAS) AF: 0.0688 AC: 2732 AN: 39694

South Asian (SAS) AF: 0.289 AC: 24893 AN: 86244

European-Finnish (FIN) AF: 0.347 AC: 18424 AN: 53076

Middle Eastern (MID) AF: 0.356 AC: 2054 AN: 5766

European-Non Finnish (NFE) AF: 0.390 AC: 433855 AN: 1111542

Other (OTH) AF: 0.346 AC: 20877 AN: 60356

GnomAD4 genome AF: 0.284 AC: 43177 AN: 152118 Hom.: 7396 Cov.: 34 AF XY: 0.280 AC XY: 20820 AN XY: 74334

African (AFR) AF: 0.106 AC: 4404 AN: 41522

American (AMR) AF: 0.296 AC: 4529 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1331 AN: 3470

East Asian (EAS) AF: 0.0840 AC: 433 AN: 5152

South Asian (SAS) AF: 0.274 AC: 1320 AN: 4824

European-Finnish (FIN) AF: 0.348 AC: 3679 AN: 10578

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.389 AC: 26434 AN: 67950

Other (OTH) AF: 0.306 AC: 648 AN: 2116

Alfa AF: 0.274 Hom.: 1148

Bravo AF: 0.272

EpiCase AF: 0.394

EpiControl AF: 0.396

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.17
DANN	Benign	0.55
PhyloP100		-1.4
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: rs1047006; hg19: chr6-146755560; COSMIC: COSV51131809;