6-146434188-T-C

Position:

chr6-146434188-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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. 15/20 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 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=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/exons	MANE	Protein	UniProt
GRM1	NM_001278064.2 linkuse as main transcript	c.2977T>C	p.Ser993Pro	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.2977T>C	p.Ser993Pro	missense_variant	8/8	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

GnomAD3 exomes

AF:

0.521

AC:

129672

AN:

249042

Hom.:

34812

AF XY:

0.525

AC XY:

70692

AN XY:

134770

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 SAS exome

AF:

0.601

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

Gnomad4 AFR exome

AF:

0.707

Gnomad4 AMR exome

AF:

0.407

Gnomad4 ASJ exome

AF:

0.568

Gnomad4 EAS exome

AF:

0.494

Gnomad4 SAS exome

AF:

0.600

Gnomad4 FIN exome

AF:

0.449

Gnomad4 NFE exome

AF:

0.523

Gnomad4 OTH exome

AF:

0.544

GnomAD4 genome

AF:

0.568

AC:

86437

AN:

152088

Hom.:

25204

Cov.:

AF XY:

0.564

AC XY:

41909

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.704

Gnomad4 AMR

AF:

0.495

Gnomad4 ASJ

AF:

0.566

Gnomad4 EAS

AF:

0.517

Gnomad4 SAS

AF:

0.603

Gnomad4 FIN

AF:

0.450

Gnomad4 NFE

AF:

0.523

Gnomad4 OTH

AF:

0.572

Alfa

AF:

0.547

Hom.:

18778

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

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 15, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2019	This variant is associated with the following publications: (PMID: 25062106, 24442360) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

Autosomal recessive spinocerebellar ataxia 13

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Spinocerebellar ataxia 44

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

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

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

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

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