Genetic Variant GRM3:c.1325-16183G>A (chr7-86822656-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000840.3(GRM3):c.1325-16183G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.028 in 152,218 control chromosomes in the GnomAD database, including 103 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 0.028 ( 103 hom., cov: 32)

Consequence

GRM3
NM_000840.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.714

Publications

4 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:

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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=-0.92).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.028 (4269/152218) while in subpopulation NFE AF = 0.0469 (3186/67996). AF 95% confidence interval is 0.0455. There are 103 homozygotes in GnomAd4. There are 1945 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 4269 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
GRM3	NM_000840.3 link	c.1325-16183G>A	intron_variant	Intron 3 of 5	ENST00000361669.7	NP_000831.2	Q14832-1A4D1D0
GRM3	NM_001363522.2 link	c.1325-27714G>A	intron_variant	Intron 3 of 4		NP_001350451.1
GRM3	XM_047420268.1 link	c.1325-16183G>A	intron_variant	Intron 4 of 6		XP_047276224.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM3	ENST00000361669.7 link	c.1325-16183G>A		intron_variant	Intron 3 of 5	1	NM_000840.3	ENSP00000355316.2		Q14832-1
GRM3	ENST00000439827.1 link	c.1325-27714G>A		intron_variant	Intron 3 of 4	1		ENSP00000398767.1		Q14832-2

Frequencies

GnomAD3 genomes

AF:

0.0281

AC:

4270

AN:

152100

Hom.:

103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00823

Gnomad AMI

AF:

0.0625

Gnomad AMR

AF:

0.0128

Gnomad ASJ

AF:

0.0136

Gnomad EAS

AF:

0.0114

Gnomad SAS

AF:

0.00622

Gnomad FIN

AF:

0.0299

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0469

Gnomad OTH

AF:

0.0178

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0280

AC:

4269

AN:

152218

Hom.:

103

Cov.:

AF XY:

0.0261

AC XY:

1945

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00821

AC:

341

AN:

41552

American (AMR)

AF:

0.0127

AC:

194

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0136

AC:

AN:

3466

East Asian (EAS)

AF:

0.0114

AC:

AN:

5182

South Asian (SAS)

AF:

0.00622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0299

AC:

317

AN:

10600

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0469

AC:

3186

AN:

67996

Other (OTH)

AF:

0.0176

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

216

431

647

862

1078

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0331

Hom.:

Bravo

AF:

0.0268

Asia WGS

AF:

0.00924

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

1.6

(source)

DANN

Benign

0.70

PhyloP100

0.71

Mutation Taster

=100/0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over