rs2941

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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 (★★).

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

Publications

22 publications found

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 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

GRM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM1	NM_001278064.2 link	c.2785G>A	p.Val929Ile	missense_variant	Exon 8 of 8	ENST00000282753.6	NP_001264993.1	Q13255-1Q59HC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM1	ENST00000282753.6 link	c.2785G>A	p.Val929Ile	missense_variant	Exon 8 of 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

GnomAD2 exomes

AF:

0.0129

AC:

3246

AN:

251446

AF XY:

0.0133

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 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

African (AFR)

AF:

0.00305

AC:

102

AN:

33478

American (AMR)

AF:

0.00776

AC:

347

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0204

AC:

532

AN:

26130

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0118

AC:

1014

AN:

86256

European-Finnish (FIN)

AF:

0.0138

AC:

738

AN:

53386

Middle Eastern (MID)

AF:

0.0180

AC:

104

AN:

5768

European-Non Finnish (NFE)

AF:

0.0180

AC:

19976

AN:

1111840

Other (OTH)

AF:

0.0176

AC:

1060

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

1299

2599

3898

5198

6497

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0119

AC:

1811

AN:

152294

Hom.:

Cov.:

AF XY:

0.0120

AC XY:

892

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00298

AC:

124

AN:

41562

American (AMR)

AF:

0.00850

AC:

130

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0184

AC:

AN:

3470

East Asian (EAS)

AF:

0.000581

AC:

AN:

5160

South Asian (SAS)

AF:

0.0120

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0143

AC:

152

AN:

10624

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0181

AC:

1234

AN:

68030

Other (OTH)

AF:

0.0156

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

192

288

384

480

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0162

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

Apr 27, 2024

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Dec 13, 2023

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GRM1-related disorder

Benign:1

Sep 06, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

6.5

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

Mutation Taster

=91/9

polymorphism

(source)

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

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rs2941

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over