rs362821

Variant names:

• chr6-146437188-T-C
• rs362821
• NM_001278064.2:c.*2392T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001278064.2(GRM1):​c.*2392T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.505 in 151,920 control chromosomes in the GnomAD database, including 19,425 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 0.50 (19425 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: GRM1 NM_001278064.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.827
• Publications: 4 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

ENSG00000304271 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM1	NM_001278064.2	c.*2392T>C		3_prime_UTR_variant	Exon 8 of 8	ENST00000282753.6	NP_001264993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM1	ENST00000282753.6	c.*2392T>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_001278064.2	ENSP00000282753.1

Frequencies

GnomAD3 genomes AF: 0.504 AC: 76581 AN: 151804 Hom.: 19398 Cov.: 32

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.472

Gnomad AMR AF: 0.469

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.518

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.512

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.505 AC: 76644 AN: 151920 Hom.: 19425 Cov.: 32 AF XY: 0.502 AC XY: 37274 AN XY: 74234

African (AFR) AF: 0.485 AC: 20110 AN: 41426

American (AMR) AF: 0.468 AC: 7158 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1958 AN: 3466

East Asian (EAS) AF: 0.520 AC: 2675 AN: 5146

South Asian (SAS) AF: 0.610 AC: 2932 AN: 4810

European-Finnish (FIN) AF: 0.447 AC: 4713 AN: 10540

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

European-Non Finnish (NFE) AF: 0.522 AC: 35444 AN: 67936

Other (OTH) AF: 0.515 AC: 1085 AN: 2106

Alfa AF: 0.509 Hom.: 9382

Bravo AF: 0.501

Asia WGS AF: 0.573 AC: 1989 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	4.9
DANN	Benign	0.82
PhyloP100		0.83
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: rs362821; hg19: chr6-146758324;