rs41305288

chr6-146399224-C-Achr6-146399224-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PP2 PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001278064.2(GRM1):c.2185C>A(p.Pro729Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0157 in 1,613,820 control chromosomes in the GnomAD database, including 263 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (19 hom., cov: 32)
  • Exomes 𝑓: 0.016 (244 hom.)
• Consequence: GRM1 NM_001278064.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.00

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 -18 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GRM1
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.012637019).
• BP6: Variant 6-146399224-C-A is Benign according to our data. Variant chr6-146399224-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 995109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-146399224-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0128 (1948/152138) while in subpopulation SAS AF= 0.0227 (109/4808). AF 95% confidence interval is 0.0192. There are 19 homozygotes in gnomad4. There are 1023 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM1	NM_001278064.2	c.2185C>A	p.Pro729Thr	missense_variant	7/8	ENST00000282753.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM1	ENST00000282753.6	c.2185C>A	p.Pro729Thr	missense_variant	7/8	1	NM_001278064.2	P1

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1944 AN: 152020 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0222

Gnomad FIN AF: 0.0318

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0161

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.0165 AC: 4142 AN: 251456 Hom.: 55 AF XY: 0.0178 AC XY: 2422 AN XY: 135900

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00951

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0228

Gnomad FIN exome AF: 0.0382

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0248

GnomAD4 exome AF: 0.0160 AC: 23444 AN: 1461682 Hom.: 244 Cov.: 34 AF XY: 0.0163 AC XY: 11832 AN XY: 727154

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.00964

Gnomad4 ASJ exome AF: 0.0109

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0228

Gnomad4 FIN exome AF: 0.0407

Gnomad4 NFE exome AF: 0.0155

Gnomad4 OTH exome AF: 0.0166

GnomAD4 genome AF: 0.0128 AC: 1948 AN: 152138 Hom.: 19 Cov.: 32 AF XY: 0.0138 AC XY: 1023 AN XY: 74356

Gnomad4 AFR AF: 0.00289

Gnomad4 AMR AF: 0.0113

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0227

Gnomad4 FIN AF: 0.0318

Gnomad4 NFE AF: 0.0161

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0150 Hom.: 35

Bravo AF: 0.00998

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.0153 AC: 132

ExAC AF: 0.0172 AC: 2089

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0181

EpiControl AF: 0.0194

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	See Variant Classification Assertion Criteria. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 02, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.013	T;T;T;T;T
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.2	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.8	D;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Benign	0.038	D;D;D;D;D
Sift4G	Uncertain	0.058	T;D;T;D;T
Polyphen		0.99	D;D;.;D;D
Vest4		0.47
MPC		1.7
ClinPred		0.024	T
GERP RS		5.5
Varity_R		0.75
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs41305288; hg19: chr6-146720360;