6-146436075-G-T

Variant names:

• chr6-146436075-G-T
• rs3804293
• NM_001278064.2:c.*1279G>T

Variant summary

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

The NM_001278064.2(GRM1):​c.*1279G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.603 in 151,942 control chromosomes in the GnomAD database, including 28,360 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 0.60 (28316 hom., cov: 32)
  • Exomes 𝑓: 0.45 (44 hom.)
• Consequence: GRM1 NM_001278064.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.760
• Publications: 8 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM1	NM_001278064.2	c.*1279G>T		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.*1279G>T		3_prime_UTR_variant	Exon 8 of 8	1	NM_001278064.2	ENSP00000282753.1

Frequencies

GnomAD3 genomes AF: 0.603 AC: 91300 AN: 151386 Hom.: 28269 Cov.: 32

Gnomad AFR AF: 0.752

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.528

Gnomad ASJ AF: 0.605

Gnomad EAS AF: 0.589

Gnomad SAS AF: 0.657

Gnomad FIN AF: 0.467

Gnomad MID AF: 0.548

Gnomad NFE AF: 0.549

Gnomad OTH AF: 0.600

GnomAD4 exome AF: 0.447 AC: 196 AN: 438 Hom.: 44 Cov.: 0 AF XY: 0.436 AC XY: 115 AN XY: 264

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) AF: 0.447 AC: 192 AN: 430

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.250 AC: 1 AN: 4

Other (OTH) AF: 0.750 AC: 3 AN: 4

GnomAD4 genome AF: 0.603 AC: 91404 AN: 151504 Hom.: 28316 Cov.: 32 AF XY: 0.599 AC XY: 44351 AN XY: 73994

African (AFR) AF: 0.752 AC: 31110 AN: 41350

American (AMR) AF: 0.527 AC: 8036 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.605 AC: 2099 AN: 3468

East Asian (EAS) AF: 0.590 AC: 3034 AN: 5144

South Asian (SAS) AF: 0.658 AC: 3159 AN: 4804

European-Finnish (FIN) AF: 0.467 AC: 4878 AN: 10438

Middle Eastern (MID) AF: 0.545 AC: 157 AN: 288

European-Non Finnish (NFE) AF: 0.549 AC: 37185 AN: 67766

Other (OTH) AF: 0.603 AC: 1262 AN: 2094

Alfa AF: 0.576 Hom.: 68637

Bravo AF: 0.610

Asia WGS AF: 0.632 AC: 2198 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.57
DANN	Benign	0.60
PhyloP100		-0.76
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: rs3804293; hg19: chr6-146757211;