chr6-146434706-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001278064.2(GRM1):c.3495C>A(p.Pro1165Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 1,602,804 control chromosomes in the GnomAD database, including 226,687 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.56 ( 24251 hom., cov: 33)

Exomes 𝑓: 0.53 ( 202436 hom. )

Consequence

GRM1
NM_001278064.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -7.05

Publications

17 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 6-146434706-C-A is Benign according to our data. Variant chr6-146434706-C-A is described in ClinVar as Benign. ClinVar VariationId is 129213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-7.05 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM1	NM_001278064.2 link	c.3495C>A	p.Pro1165Pro	synonymous_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.3495C>A	p.Pro1165Pro	synonymous_variant	Exon 8 of 8	1	NM_001278064.2	ENSP00000282753.1		Q13255-1

Frequencies

GnomAD3 genomes

AF:

0.559

AC:

84959

AN:

152006

Hom.:

24226

Cov.:

show subpopulations

Gnomad AFR

AF:

0.673

Gnomad AMI

AF:

0.471

Gnomad AMR

AF:

0.492

Gnomad ASJ

AF:

0.565

Gnomad EAS

AF:

0.519

Gnomad SAS

AF:

0.603

Gnomad FIN

AF:

0.447

Gnomad MID

AF:

0.500

Gnomad NFE

AF:

0.523

Gnomad OTH

AF:

0.562

GnomAD2 exomes

AF:

0.520

AC:

124677

AN:

239870

AF XY:

0.524

show subpopulations

Gnomad AFR exome

AF:

0.678

Gnomad AMR exome

AF:

0.396

Gnomad ASJ exome

AF:

0.573

Gnomad EAS exome

AF:

0.515

Gnomad FIN exome

AF:

0.447

Gnomad NFE exome

AF:

0.519

Gnomad OTH exome

AF:

0.526

GnomAD4 exome

AF:

0.526

AC:

762612

AN:

1450680

Hom.:

202436

Cov.:

AF XY:

0.528

AC XY:

381525

AN XY:

722168

show subpopulations

African (AFR)

AF:

0.676

AC:

22641

AN:

33468

American (AMR)

AF:

0.405

AC:

18097

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.568

AC:

14839

AN:

26130

East Asian (EAS)

AF:

0.496

AC:

19699

AN:

39694

South Asian (SAS)

AF:

0.600

AC:

51715

AN:

86252

European-Finnish (FIN)

AF:

0.447

AC:

19058

AN:

42644

Middle Eastern (MID)

AF:

0.570

AC:

3284

AN:

5766

European-Non Finnish (NFE)

AF:

0.522

AC:

580619

AN:

1111686

Other (OTH)

AF:

0.541

AC:

32660

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

22342

44683

67025

89366

111708

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16696

33392

50088

66784

83480

<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:

0.559

AC:

85025

AN:

152124

Hom.:

24251

Cov.:

AF XY:

0.555

AC XY:

41276

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.673

AC:

27929

AN:

41494

American (AMR)

AF:

0.491

AC:

7515

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.565

AC:

1961

AN:

3472

East Asian (EAS)

AF:

0.521

AC:

2684

AN:

5154

South Asian (SAS)

AF:

0.604

AC:

2915

AN:

4826

European-Finnish (FIN)

AF:

0.447

AC:

4737

AN:

10594

Middle Eastern (MID)

AF:

0.490

AC:

144

AN:

294

European-Non Finnish (NFE)

AF:

0.522

AC:

35515

AN:

67972

Other (OTH)

AF:

0.566

AC:

1196

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1915

3830

5746

7661

9576

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

734

1468

2202

2936

3670

<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:

0.501

Hom.:

5145

Bravo

AF:

0.563

Asia WGS

AF:

0.579

AC:

2014

AN:

3478

EpiCase

AF:

0.535

EpiControl

AF:

0.536

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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

- -

Aug 09, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

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. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autosomal recessive spinocerebellar ataxia 13

Benign:2

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

- -

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

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.31

(source)

DANN

Benign

0.90

PhyloP100

-7.1

Mutation Taster

=100/0

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