rs41305288

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.00

Publications

18 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 -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PROVEAN, REVEL, 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 Benign/Likely_benign. ClinVar VariationId is 995109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

BS2

High Homozygotes in GnomAd4 at 19 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM1	NM_001278064.2 link	c.2185C>A	p.Pro729Thr	missense_variant	Exon 7 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.2185C>A	p.Pro729Thr	missense_variant	Exon 7 of 8	1	NM_001278064.2	ENSP00000282753.1		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

GnomAD2 exomes

AF:

0.0165

AC:

4142

AN:

251456

AF XY:

0.0178

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 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

African (AFR)

AF:

0.00272

AC:

AN:

33476

American (AMR)

AF:

0.00964

AC:

431

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

286

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0228

AC:

1969

AN:

86254

European-Finnish (FIN)

AF:

0.0407

AC:

2176

AN:

53418

Middle Eastern (MID)

AF:

0.0395

AC:

228

AN:

5768

European-Non Finnish (NFE)

AF:

0.0155

AC:

17256

AN:

1111820

Other (OTH)

AF:

0.0166

AC:

1004

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

1459

2919

4378

5838

7297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

644

1288

1932

2576

3220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0128

AC:

1948

AN:

152138

Hom.:

Cov.:

AF XY:

0.0138

AC XY:

1023

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.00289

AC:

120

AN:

41500

American (AMR)

AF:

0.0113

AC:

173

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5158

South Asian (SAS)

AF:

0.0227

AC:

109

AN:

4808

European-Finnish (FIN)

AF:

0.0318

AC:

337

AN:

10586

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0161

AC:

1098

AN:

68010

Other (OTH)

AF:

0.0227

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

186

279

372

465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0143

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

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Jan 09, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

6.0

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

Mutation Taster

=88/12

polymorphism (auto)

(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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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