rs41305288

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PP2PP3BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000282753.6(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
ENST00000282753.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 6.00

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GRM1. . Gene score misZ 2.5817 (greater than the threshold 3.09). Trascript score misZ 3.6372 (greater than threshold 3.09). GenCC has associacion of gene with spinocerebellar ataxia 44, autosomal recessive spinocerebellar ataxia 13.

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 GnomAd4 at 19 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM1	NM_001278064.2 linkuse as main transcript	c.2185C>A	p.Pro729Thr	missense_variant	7/8	ENST00000282753.6	NP_001264993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRM1	ENST00000282753.6 linkuse as main transcript	c.2185C>A	p.Pro729Thr	missense_variant	7/8	1	NM_001278064.2	ENSP00000282753	P1	Q13255-1

Frequencies

GnomAD3 genomes

AF:

0.0128

AC:

1944

AN:

152020

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0178

AC XY:

2422

AN XY:

135900

show subpopulations

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.:

AF XY:

0.0163

AC XY:

11832

AN XY:

727154

show subpopulations

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.:

Cov.:

AF XY:

0.0138

AC XY:

1023

AN XY:

74356

show subpopulations

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.:

Bravo

AF:

0.00998

TwinsUK

AF:

0.0148

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.0153

AC:

132

ExAC

AF:

0.0172

AC:

2089

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.0181

EpiControl

AF:

0.0194

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

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

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

.;D;.;D;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

.;D;D;.;D

MetaRNN

Benign

0.013

T;T;T;T;T

MetaSVM

Pathogenic

0.84

MutationAssessor

Pathogenic

3.2

M;M;M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.72

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over