6-146436074-T-C

Variant names:

• chr6-146436074-T-C
• rs3804294
• NM_001278064.2:c.*1278T>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.*1278T>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 0.641 in 152,028 control chromosomes in the GnomAD database, including 33,122 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 (33078 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: -2.16
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.879 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM1	NM_001278064.2	c.*1278T>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.*1278T>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_001278064.2	ENSP00000282753.1

Frequencies

GnomAD3 genomes AF: 0.641 AC: 97149 AN: 151472 Hom.: 33020 Cov.: 32

Gnomad AFR AF: 0.886

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.540

Gnomad ASJ AF: 0.605

Gnomad EAS AF: 0.588

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.549

Gnomad OTH AF: 0.628

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: 0.642 AC: 97264 AN: 151590 Hom.: 33078 Cov.: 32 AF XY: 0.636 AC XY: 47118 AN XY: 74034

African (AFR) AF: 0.886 AC: 36673 AN: 41372

American (AMR) AF: 0.539 AC: 8225 AN: 15250

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

East Asian (EAS) AF: 0.590 AC: 3034 AN: 5146

South Asian (SAS) AF: 0.658 AC: 3163 AN: 4806

European-Finnish (FIN) AF: 0.466 AC: 4882 AN: 10468

Middle Eastern (MID) AF: 0.565 AC: 165 AN: 292

European-Non Finnish (NFE) AF: 0.549 AC: 37219 AN: 67782

Other (OTH) AF: 0.630 AC: 1320 AN: 2096

Alfa AF: 0.647 Hom.: 8137

Bravo AF: 0.654

Asia WGS AF: 0.640 AC: 2225 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.80
DANN	Benign	0.28
PhyloP100		-2.2
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: rs3804294; hg19: chr6-146757210;