6-146028514-C-T

Variant names:

• chr6-146028514-C-T
• rs854145
• ENST00000492807.6:c.-320-684C>T

Variant summary

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

The ENST00000492807.6(GRM1):​c.-320-684C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 151,266 control chromosomes in the GnomAD database, including 12,549 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 0.40 (12549 hom., cov: 29)
• Consequence: GRM1 ENST00000492807.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.210
• 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

ENSG00000299793 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM1	NM_001278065.2	c.-320-684C>T		intron_variant	Intron 1 of 9		NP_001264994.1
GRM1	XM_011535782.2	c.-323-681C>T		intron_variant	Intron 1 of 8		XP_011534084.1
GRM1	XM_017010783.2	c.-320-684C>T		intron_variant	Intron 1 of 8		XP_016866272.1
GRM1	XM_017010784.2	c.-320-684C>T		intron_variant	Intron 1 of 8		XP_016866273.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM1	ENST00000492807.6	c.-320-684C>T		intron_variant	Intron 1 of 9	1		ENSP00000424095.1
GRM1	ENST00000361719.6	c.-320-684C>T		intron_variant	Intron 1 of 8	5		ENSP00000354896.2
GRM1	ENST00000706833.1	c.-323-681C>T		intron_variant	Intron 1 of 8			ENSP00000516579.1

Frequencies

GnomAD3 genomes AF: 0.403 AC: 60942 AN: 151146 Hom.: 12533 Cov.: 29

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.472

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.353

Gnomad SAS AF: 0.500

Gnomad FIN AF: 0.487

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.410

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

GnomAD4 genome AF: 0.403 AC: 60987 AN: 151266 Hom.: 12549 Cov.: 29 AF XY: 0.406 AC XY: 29958 AN XY: 73838

African (AFR) AF: 0.348 AC: 14363 AN: 41242

American (AMR) AF: 0.315 AC: 4790 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1447 AN: 3460

East Asian (EAS) AF: 0.353 AC: 1767 AN: 5000

South Asian (SAS) AF: 0.500 AC: 2389 AN: 4782

European-Finnish (FIN) AF: 0.487 AC: 5084 AN: 10434

Middle Eastern (MID) AF: 0.510 AC: 149 AN: 292

European-Non Finnish (NFE) AF: 0.438 AC: 29695 AN: 67822

Other (OTH) AF: 0.416 AC: 876 AN: 2104

Alfa AF: 0.263 Hom.: 640

Bravo AF: 0.387

Asia WGS AF: 0.458 AC: 1593 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.4
DANN	Benign	0.70
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs854145; hg19: chr6-146349650;