Genetic Variant GRM3:p.Ala293Ala (chr7-86786671-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

The NM_000840.3(GRM3):c.879C>T(p.Ala293Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0624 in 1,612,066 control chromosomes in the GnomAD database, including 3,624 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.051 ( 277 hom., cov: 32)

Exomes 𝑓: 0.064 ( 3347 hom. )

Consequence

GRM3
NM_000840.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0260

Publications

20 publications found

Variant links:

Genes affected

GRM3 (HGNC:4595): (glutamate metabotropic receptor 3) 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 metabotropic glutamate receptors are a family of G protein-coupled receptors, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group I includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3 while Group III includes GRM4, GRM6, GRM7 and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities. [provided by RefSeq, Jul 2008]

GRM3 links:

GRM3-AS1 (HGNC:40264): (GRM3 antisense RNA 1)

GRM3-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP7

Synonymous conserved (PhyloP=-0.026 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0964 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM3	NM_000840.3 link	c.879C>T	p.Ala293Ala	synonymous_variant	Exon 3 of 6	ENST00000361669.7	NP_000831.2	Q14832-1A4D1D0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM3	ENST00000361669.7 link	c.879C>T	p.Ala293Ala	synonymous_variant	Exon 3 of 6	1	NM_000840.3	ENSP00000355316.2		Q14832-1

Frequencies

GnomAD3 genomes

AF:

0.0511

AC:

7786

AN:

152258

Hom.:

277

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0119

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.0709

Gnomad ASJ

AF:

0.138

Gnomad EAS

AF:

0.0620

Gnomad SAS

AF:

0.103

Gnomad FIN

AF:

0.0459

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0619

Gnomad OTH

AF:

0.0635

GnomAD2 exomes

AF:

0.0681

AC:

16786

AN:

246570

AF XY:

0.0713

show subpopulations

Gnomad AFR exome

AF:

0.00951

Gnomad AMR exome

AF:

0.0761

Gnomad ASJ exome

AF:

0.146

Gnomad EAS exome

AF:

0.0671

Gnomad FIN exome

AF:

0.0486

Gnomad NFE exome

AF:

0.0596

Gnomad OTH exome

AF:

0.0760

GnomAD4 exome

AF:

0.0635

AC:

92745

AN:

1459690

Hom.:

3347

Cov.:

AF XY:

0.0656

AC XY:

47656

AN XY:

726266

show subpopulations

African (AFR)

AF:

0.00965

AC:

323

AN:

33476

American (AMR)

AF:

0.0750

AC:

3351

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.144

AC:

3767

AN:

26104

East Asian (EAS)

AF:

0.0564

AC:

2237

AN:

39696

South Asian (SAS)

AF:

0.106

AC:

9177

AN:

86226

European-Finnish (FIN)

AF:

0.0476

AC:

2450

AN:

51502

Middle Eastern (MID)

AF:

0.117

AC:

675

AN:

5768

European-Non Finnish (NFE)

AF:

0.0597

AC:

66413

AN:

1111860

Other (OTH)

AF:

0.0721

AC:

4352

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

5730

11460

17191

22921

28651

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2570

5140

7710

10280

12850

<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:

0.0511

AC:

7785

AN:

152376

Hom.:

277

Cov.:

AF XY:

0.0524

AC XY:

3905

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.0119

AC:

494

AN:

41594

American (AMR)

AF:

0.0709

AC:

1086

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.138

AC:

480

AN:

3472

East Asian (EAS)

AF:

0.0618

AC:

320

AN:

5180

South Asian (SAS)

AF:

0.104

AC:

502

AN:

4832

European-Finnish (FIN)

AF:

0.0459

AC:

488

AN:

10624

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0619

AC:

4213

AN:

68038

Other (OTH)

AF:

0.0638

AC:

135

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

383

766

1150

1533

1916

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<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:

0.0612

Hom.:

454

Bravo

AF:

0.0502

Asia WGS

AF:

0.0610

AC:

213

AN:

3478

EpiCase

AF:

0.0672

EpiControl

AF:

0.0673

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

-0.026

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

Computational scores

Splicing

Publications

Other links and lift over