NM_001278064.2:c.1729+4946C>A

Variant names:

• chr6-146391962-C-A
• rs362853
• NM_001278064.2:c.1729+4946C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001278064.2(GRM1):​c.1729+4946C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 151,884 control chromosomes in the GnomAD database, including 14,570 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.44 (14570 hom., cov: 32)
• Consequence: GRM1 NM_001278064.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0780
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM1	NM_001278064.2	c.1729+4946C>A		intron_variant	Intron 6 of 7	ENST00000282753.6	NP_001264993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM1	ENST00000282753.6	c.1729+4946C>A		intron_variant	Intron 6 of 7	1	NM_001278064.2	ENSP00000282753.1

Frequencies

GnomAD3 genomes AF: 0.436 AC: 66122 AN: 151766 Hom.: 14552 Cov.: 32

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.363

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.475

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.436 AC: 66191 AN: 151884 Hom.: 14570 Cov.: 32 AF XY: 0.434 AC XY: 32224 AN XY: 74214

African (AFR) AF: 0.499 AC: 20670 AN: 41420

American (AMR) AF: 0.370 AC: 5634 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1765 AN: 3464

East Asian (EAS) AF: 0.364 AC: 1876 AN: 5152

South Asian (SAS) AF: 0.384 AC: 1852 AN: 4822

European-Finnish (FIN) AF: 0.404 AC: 4264 AN: 10554

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.421 AC: 28601 AN: 67926

Other (OTH) AF: 0.476 AC: 1003 AN: 2108

Alfa AF: 0.429 Hom.: 7669

Bravo AF: 0.438

Asia WGS AF: 0.369 AC: 1286 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.7
DANN	Benign	0.61
PhyloP100		-0.078
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: rs362853; hg19: chr6-146713098;