6-146434188-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001278064.2(GRM1):c.2977T>C(p.Ser993Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.531 in 1,612,248 control chromosomes in the GnomAD database, including 229,896 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 25204 hom., cov: 33)

Exomes 𝑓: 0.53 ( 204692 hom. )

Consequence

GRM1
NM_001278064.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.127

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 was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=2.9640603E-6).

BP6

Variant 6-146434188-T-C is Benign according to our data. Variant chr6-146434188-T-C is described in ClinVar as [Benign]. Clinvar id is 129210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-146434188-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM1	NM_001278064.2 link	c.2977T>C	p.Ser993Pro	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.2977T>C	p.Ser993Pro	missense_variant	Exon 8 of 8	1	NM_001278064.2	ENSP00000282753.1		Q13255-1

Frequencies

GnomAD3 genomes

AF:

0.568

AC:

86347

AN:

151972

Hom.:

25163

Cov.:

show subpopulations

Gnomad AFR

AF:

0.704

Gnomad AMI

AF:

0.474

Gnomad AMR

AF:

0.496

Gnomad ASJ

AF:

0.566

Gnomad EAS

AF:

0.516

Gnomad SAS

AF:

0.602

Gnomad FIN

AF:

0.450

Gnomad MID

AF:

0.506

Gnomad NFE

AF:

0.523

Gnomad OTH

AF:

0.569

GnomAD2 exomes

AF:

0.521

AC:

129672

AN:

249042

AF XY:

0.525

show subpopulations

Gnomad AFR exome

AF:

0.711

Gnomad AMR exome

AF:

0.398

Gnomad ASJ exome

AF:

0.573

Gnomad EAS exome

AF:

0.510

Gnomad FIN exome

AF:

0.448

Gnomad NFE exome

AF:

0.520

Gnomad OTH exome

AF:

0.528

GnomAD4 exome

AF:

0.527

AC:

769036

AN:

1460160

Hom.:

204692

Cov.:

AF XY:

0.529

AC XY:

384356

AN XY:

726230

show subpopulations

African (AFR)

AF:

0.707

AC:

23646

AN:

33432

American (AMR)

AF:

0.407

AC:

18203

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.568

AC:

14812

AN:

26096

East Asian (EAS)

AF:

0.494

AC:

19598

AN:

39680

South Asian (SAS)

AF:

0.600

AC:

51747

AN:

86204

European-Finnish (FIN)

AF:

0.449

AC:

23962

AN:

53328

Middle Eastern (MID)

AF:

0.575

AC:

3314

AN:

5762

European-Non Finnish (NFE)

AF:

0.523

AC:

580924

AN:

1110650

Other (OTH)

AF:

0.544

AC:

32830

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

21884

43767

65651

87534

109418

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.568

AC:

86437

AN:

152088

Hom.:

25204

Cov.:

AF XY:

0.564

AC XY:

41909

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.704

AC:

29245

AN:

41518

American (AMR)

AF:

0.495

AC:

7569

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.566

AC:

1965

AN:

3472

East Asian (EAS)

AF:

0.517

AC:

2651

AN:

5128

South Asian (SAS)

AF:

0.603

AC:

2909

AN:

4824

European-Finnish (FIN)

AF:

0.450

AC:

4746

AN:

10558

Middle Eastern (MID)

AF:

0.497

AC:

146

AN:

294

European-Non Finnish (NFE)

AF:

0.523

AC:

35567

AN:

67986

Other (OTH)

AF:

0.572

AC:

1208

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1911

3821

5732

7642

9553

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.550

Hom.:

26388

Bravo

AF:

0.573

TwinsUK

AF:

0.523

AC:

1941

ALSPAC

AF:

0.529

AC:

2040

ESP6500AA

AF:

0.710

AC:

3129

ESP6500EA

AF:

0.533

AC:

4581

ExAC

AF:

0.530

AC:

64327

Asia WGS

AF:

0.578

AC:

2010

AN:

3478

EpiCase

AF:

0.536

EpiControl

AF:

0.537

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Sep 25, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25062106, 24442360) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive spinocerebellar ataxia 13

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Spinocerebellar ataxia 44

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.085

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0058

LIST_S2

Benign

0.18

T;.

MetaRNN

Benign

0.0000030

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.90

N;N

PhyloP100

0.13

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.10

N;N

REVEL

Benign

0.22

Sift

Benign

0.82

T;T

Sift4G

Benign

0.38

T;T

Polyphen

0.0

B;B

Vest4

0.0080

MPC

0.87

ClinPred

0.00072

GERP RS

3.4

Varity_R

0.099

gMVP

0.17

Mutation Taster

=96/4

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

Loading publications...

6-146434188-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over