chr6-146434425-C-G

Variant names:

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.3214C>G(p.Pro1072Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,613,760 control chromosomes in the GnomAD database, including 21 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1072S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0060 ( 10 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 11 hom. )

Consequence

GRM1
NM_001278064.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.36

Publications

4 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=0.004937917).

BP6

Variant 6-146434425-C-G is Benign according to our data. Variant chr6-146434425-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 445990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-146434425-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 445990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-146434425-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 445990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-146434425-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 445990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-146434425-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 445990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00605 (921/152352) while in subpopulation AFR AF = 0.0169 (701/41590). AF 95% confidence interval is 0.0158. There are 10 homozygotes in GnomAd4. There are 433 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM1	NM_001278064.2 link	c.3214C>G	p.Pro1072Ala	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.3214C>G	p.Pro1072Ala	missense_variant	Exon 8 of 8	1	NM_001278064.2	ENSP00000282753.1		Q13255-1

Frequencies

GnomAD3 genomes

AF:

0.00603

AC:

918

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0168

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00425

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00253

AC:

621

AN:

245696

AF XY:

0.00225

show subpopulations

Gnomad AFR exome

AF:

0.0151

Gnomad AMR exome

AF:

0.00284

Gnomad ASJ exome

AF:

0.0143

Gnomad EAS exome

AF:

0.000166

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00103

Gnomad OTH exome

AF:

0.00282

GnomAD4 exome

AF:

0.00160

AC:

2339

AN:

1461408

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

1138

AN XY:

726994

show subpopulations

African (AFR)

AF:

0.0167

AC:

558

AN:

33474

American (AMR)

AF:

0.00282

AC:

126

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0134

AC:

349

AN:

26110

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39692

South Asian (SAS)

AF:

0.000417

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53168

Middle Eastern (MID)

AF:

0.00936

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000895

AC:

995

AN:

1111864

Other (OTH)

AF:

0.00359

AC:

217

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

157

314

470

627

784

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.00605

AC:

921

AN:

152352

Hom.:

Cov.:

AF XY:

0.00581

AC XY:

433

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0169

AC:

701

AN:

41590

American (AMR)

AF:

0.00425

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5160

South Asian (SAS)

AF:

0.00104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00116

AC:

AN:

68040

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

148

197

246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00209

Hom.:

Bravo

AF:

0.00680

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.0153

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00263

AC:

319

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00196

EpiControl

AF:

0.00119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 15, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 20, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

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;C4521563:Spinocerebellar ataxia 44

Benign:1

Aug 26, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.15

T;T

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.68

T;.

MetaRNN

Benign

0.0049

T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.34

N;N

PhyloP100

1.4

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.66

N;N

REVEL

Benign

0.11

Sift

Benign

0.080

T;T

Sift4G

Benign

0.35

T;T

Polyphen

0.0080

B;B

Vest4

0.16

MVP

0.26

MPC

0.70

ClinPred

0.0017

GERP RS

2.9

Varity_R

0.054

gMVP

0.34

Mutation Taster

=96/4

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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