7-86765277-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_000840.3(GRM3):c.132G>A(p.Leu44=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00473 in 1,613,730 control chromosomes in the GnomAD database, including 270 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (147 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (123 hom.)
• Consequence: GRM3 NM_000840.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.421

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 7-86765277-G-A is Benign according to our data. Variant chr7-86765277-G-A is described in ClinVar as [Benign]. Clinvar id is 768176.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.421 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0786 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM3	NM_000840.3	c.132G>A	p.Leu44=	synonymous_variant	2/6	ENST00000361669.7
GRM3	NM_001363522.2	c.132G>A	p.Leu44=	synonymous_variant	2/5
GRM3	XM_047420268.1	c.132G>A	p.Leu44=	synonymous_variant	3/7
GRM3	XM_017012073.3	c.132G>A	p.Leu44=	synonymous_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM3	ENST00000361669.7	c.132G>A	p.Leu44=	synonymous_variant	2/6	1	NM_000840.3	P1

Frequencies

GnomAD3 genomes AF: 0.0239 AC: 3629 AN: 152074 Hom.: 147 Cov.: 32

Gnomad AFR AF: 0.0808

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.000809

Gnomad OTH AF: 0.0249

GnomAD3 exomes AF: 0.00641 AC: 1605 AN: 250532 Hom.: 56 AF XY: 0.00461 AC XY: 624 AN XY: 135394

Gnomad AFR exome AF: 0.0807

Gnomad AMR exome AF: 0.00482

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000619

Gnomad OTH exome AF: 0.00442

GnomAD4 exome AF: 0.00274 AC: 4000 AN: 1461538 Hom.: 123 Cov.: 31 AF XY: 0.00242 AC XY: 1756 AN XY: 727078

Gnomad4 AFR exome AF: 0.0792

Gnomad4 AMR exome AF: 0.00571

Gnomad4 ASJ exome AF: 0.00256

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000502

Gnomad4 OTH exome AF: 0.00702

GnomAD4 genome AF: 0.0239 AC: 3641 AN: 152192 Hom.: 147 Cov.: 32 AF XY: 0.0234 AC XY: 1739 AN XY: 74426

Gnomad4 AFR AF: 0.0809

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000809

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0105 Hom.: 33

Bravo AF: 0.0281

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000983

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	4.2
Dann	Benign	0.74

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

LitVar

Other links and lift over

dbSNP: rs56763064; hg19: chr7-86394593;