rs2941

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001278064.2(GRM1):c.2785G>A(p.Val929Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0159 in 1,613,966 control chromosomes in the GnomAD database, including 264 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 0.012 ( 11 hom., cov: 32)

Exomes 𝑓: 0.016 ( 253 hom. )

Consequence

GRM1
NM_001278064.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 6.45

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 -19 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.0067032278).

BP6

Variant 6-146433996-G-A is Benign according to our data. Variant chr6-146433996-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 995115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-146433996-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0119 (1811/152294) while in subpopulation NFE AF= 0.0181 (1234/68030). AF 95% confidence interval is 0.0173. There are 11 homozygotes in gnomad4. There are 892 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM1	NM_001278064.2 linkuse as main transcript	c.2785G>A	p.Val929Ile	missense_variant	8/8	ENST00000282753.6	NP_001264993.1	Q13255-1Q59HC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRM1	ENST00000282753.6 linkuse as main transcript	c.2785G>A	p.Val929Ile	missense_variant	8/8	1	NM_001278064.2	ENSP00000282753.1		Q13255-1

Frequencies

GnomAD3 genomes

AF:

0.0119

AC:

1815

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00299

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00857

Gnomad ASJ

AF:

0.0184

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.0120

Gnomad FIN

AF:

0.0143

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0181

Gnomad OTH

AF:

0.0163

GnomAD3 exomes

AF:

0.0129

AC:

3246

AN:

251446

Hom.:

AF XY:

0.0133

AC XY:

1814

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00265

Gnomad AMR exome

AF:

0.00769

Gnomad ASJ exome

AF:

0.0198

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0111

Gnomad FIN exome

AF:

0.0119

Gnomad NFE exome

AF:

0.0180

Gnomad OTH exome

AF:

0.0155

GnomAD4 exome

AF:

0.0163

AC:

23876

AN:

1461672

Hom.:

253

Cov.:

AF XY:

0.0164

AC XY:

11935

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.00305

Gnomad4 AMR exome

AF:

0.00776

Gnomad4 ASJ exome

AF:

0.0204

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0118

Gnomad4 FIN exome

AF:

0.0138

Gnomad4 NFE exome

AF:

0.0180

Gnomad4 OTH exome

AF:

0.0176

GnomAD4 genome

AF:

0.0119

AC:

1811

AN:

152294

Hom.:

Cov.:

AF XY:

0.0120

AC XY:

892

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00298

Gnomad4 AMR

AF:

0.00850

Gnomad4 ASJ

AF:

0.0184

Gnomad4 EAS

AF:

0.000581

Gnomad4 SAS

AF:

0.0120

Gnomad4 FIN

AF:

0.0143

Gnomad4 NFE

AF:

0.0181

Gnomad4 OTH

AF:

0.0156

Alfa

AF:

0.0175

Hom.:

Bravo

AF:

0.0110

TwinsUK

AF:

0.0132

AC:

ALSPAC

AF:

0.0195

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0183

AC:

157

ExAC

AF:

0.0132

AC:

1599

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0179

EpiControl

AF:

0.0184

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2024	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 13, 2023

- -

GRM1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2019

This variant is classified as 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

Benign

0.098

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T

Eigen

Benign

0.087

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;.

MetaRNN

Benign

0.0067

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;L

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.23

N;N

REVEL

Benign

0.082

Sift

Benign

0.17

T;T

Sift4G

Benign

0.28

T;T

Polyphen

0.11

B;B

Vest4

0.050

MPC

0.57

ClinPred

0.035

GERP RS

5.4

Varity_R

0.19

gMVP

0.41

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