Genetic Variant GRM4:c.*151A>G (chr6-34022670-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000841.4(GRM4):c.*151A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 674,752 control chromosomes in the GnomAD database, including 24,904 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 0.32 ( 10903 hom., cov: 32)

Exomes 𝑓: 0.21 ( 14001 hom. )

Consequence

GRM4
NM_000841.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.250

Publications

18 publications found

Variant links:

Genes affected

GRM4 (HGNC:4596): (glutamate metabotropic receptor 4) 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. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

GRM4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM4	NM_000841.4 link	c.*151A>G		3_prime_UTR_variant	Exon 11 of 11	ENST00000538487.7	NP_000832.1	Q14833-1A1L4F9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM4	ENST00000538487.7 link	c.*151A>G		3_prime_UTR_variant	Exon 11 of 11	2	NM_000841.4	ENSP00000440556.1		Q14833-1

Frequencies

GnomAD3 genomes

AF:

0.317

AC:

48247

AN:

152040

Hom.:

10856

Cov.:

show subpopulations

Gnomad AFR

AF:

0.638

Gnomad AMI

AF:

0.133

Gnomad AMR

AF:

0.254

Gnomad ASJ

AF:

0.163

Gnomad EAS

AF:

0.379

Gnomad SAS

AF:

0.297

Gnomad FIN

AF:

0.183

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.165

Gnomad OTH

AF:

0.311

GnomAD4 exome

AF:

0.210

AC:

109656

AN:

522594

Hom.:

14001

Cov.:

AF XY:

0.211

AC XY:

58182

AN XY:

276146

show subpopulations

African (AFR)

AF:

0.645

AC:

9572

AN:

14840

American (AMR)

AF:

0.251

AC:

6971

AN:

27820

Ashkenazi Jewish (ASJ)

AF:

0.163

AC:

2604

AN:

16020

East Asian (EAS)

AF:

0.332

AC:

10469

AN:

31506

South Asian (SAS)

AF:

0.281

AC:

14676

AN:

52206

European-Finnish (FIN)

AF:

0.173

AC:

5991

AN:

34722

Middle Eastern (MID)

AF:

0.220

AC:

494

AN:

2246

European-Non Finnish (NFE)

AF:

0.166

AC:

52240

AN:

314590

Other (OTH)

AF:

0.232

AC:

6639

AN:

28644

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

3912

7823

11735

15646

19558

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

650

1300

1950

2600

3250

<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:

0.318

AC:

48344

AN:

152158

Hom.:

10903

Cov.:

AF XY:

0.315

AC XY:

23464

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.638

AC:

26499

AN:

41504

American (AMR)

AF:

0.254

AC:

3885

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.163

AC:

564

AN:

3470

East Asian (EAS)

AF:

0.378

AC:

1950

AN:

5154

South Asian (SAS)

AF:

0.294

AC:

1419

AN:

4830

European-Finnish (FIN)

AF:

0.183

AC:

1944

AN:

10614

Middle Eastern (MID)

AF:

0.238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.165

AC:

11233

AN:

67984

Other (OTH)

AF:

0.312

AC:

659

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1416

2832

4248

5664

7080

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

436

872

1308

1744

2180

<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:

0.234

Hom.:

13499

Bravo

AF:

0.338

Asia WGS

AF:

0.381

AC:

1323

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

6.3

(source)

DANN

Benign

0.75

PhyloP100

-0.25

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