6-146435433-T-C

Variant names:

• chr6-146435433-T-C
• rs362819
• NM_001278064.2:c.*637T>C

Variant summary

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

The NM_001278064.2(GRM1):​c.*637T>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 0.636 in 156,822 control chromosomes in the GnomAD database, including 33,695 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 0.64 (32954 hom., cov: 33)
  • Exomes 𝑓: 0.53 (741 hom.)
• Consequence: GRM1 NM_001278064.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.87 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM1	NM_001278064.2	c.*637T>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.*637T>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_001278064.2	ENSP00000282753.1

Frequencies

GnomAD3 genomes AF: 0.640 AC: 97216 AN: 151978 Hom.: 32898 Cov.: 33

Gnomad AFR AF: 0.877

Gnomad AMI AF: 0.533

Gnomad AMR AF: 0.540

Gnomad ASJ AF: 0.606

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.550

Gnomad OTH AF: 0.628

GnomAD4 exome AF: 0.526 AC: 2485 AN: 4726 Hom.: 741 Cov.: 0 AF XY: 0.520 AC XY: 1265 AN XY: 2432

African (AFR) AF: 0.955 AC: 21 AN: 22

American (AMR) AF: 0.437 AC: 550 AN: 1260

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 7 AN: 20

East Asian (EAS) AF: 0.573 AC: 102 AN: 178

South Asian (SAS) AF: 0.590 AC: 217 AN: 368

European-Finnish (FIN) AF: 0.222 AC: 4 AN: 18

Middle Eastern (MID) AF: 1.00 AC: 4 AN: 4

European-Non Finnish (NFE) AF: 0.550 AC: 1485 AN: 2700

Other (OTH) AF: 0.609 AC: 95 AN: 156

GnomAD4 genome AF: 0.640 AC: 97328 AN: 152096 Hom.: 32954 Cov.: 33 AF XY: 0.635 AC XY: 47204 AN XY: 74356

African (AFR) AF: 0.877 AC: 36410 AN: 41510

American (AMR) AF: 0.539 AC: 8239 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 2103 AN: 3468

East Asian (EAS) AF: 0.591 AC: 3046 AN: 5156

South Asian (SAS) AF: 0.658 AC: 3175 AN: 4826

European-Finnish (FIN) AF: 0.469 AC: 4968 AN: 10584

Middle Eastern (MID) AF: 0.565 AC: 166 AN: 294

European-Non Finnish (NFE) AF: 0.550 AC: 37406 AN: 67956

Other (OTH) AF: 0.630 AC: 1329 AN: 2108

Alfa AF: 0.546 Hom.: 4265

Bravo AF: 0.651

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.054
DANN	Benign	0.44
PhyloP100		-1.1
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: rs362819; hg19: chr6-146756569;