rs7760248

chr6-146159501-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS1

The NM_001278064.2(GRM1):c.854G>A(p.Arg285Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000335 in 1,614,202 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: GRM1 NM_001278064.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 9.54

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GRM1
• BP4: Computational evidence support a benign effect (MetaRNN=0.015028983).
• BP6: Variant 6-146159501-G-A is Benign according to our data. Variant chr6-146159501-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 786100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00178 (271/152356) while in subpopulation AFR AF= 0.00613 (255/41584). AF 95% confidence interval is 0.00551. There are 0 homozygotes in gnomad4. There are 152 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM1	NM_001278064.2	c.854G>A	p.Arg285Lys	missense_variant	2/8	ENST00000282753.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM1	ENST00000282753.6	c.854G>A	p.Arg285Lys	missense_variant	2/8	1	NM_001278064.2	P1

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 269 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00610

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000454 AC: 114 AN: 251180 Hom.: 0 AF XY: 0.000295 AC XY: 40 AN XY: 135744

Gnomad AFR exome AF: 0.00634

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000185 AC: 270 AN: 1461846 Hom.: 2 Cov.: 33 AF XY: 0.000140 AC XY: 102 AN XY: 727230

Gnomad4 AFR exome AF: 0.00687

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.00204 AC XY: 152 AN XY: 74504

Gnomad4 AFR AF: 0.00613

Gnomad4 AMR AF: 0.000718

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000455 Hom.: 0

Bravo AF: 0.00218

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000577 AC: 70

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 20, 2023

- -

GRM1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 26, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.015	T;T;T;T;T
MetaSVM	Uncertain	0.091	D
MutationAssessor	Benign	1.6	L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.0	N;N;N;N;N
REVEL	Pathogenic	0.71
Sift	Benign	0.11	T;T;T;T;T
Sift4G	Benign	0.18	T;D;T;D;T
Polyphen		0.57	P;P;.;P;P
Vest4		0.80
MVP		0.89
MPC		0.83
ClinPred		0.085	T
GERP RS		5.3
Varity_R		0.48
gMVP		0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs7760248; hg19: chr6-146480637;