3-6861610-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000844.4(GRM7):c.222C>T(p.Asn74=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,610,478 control chromosomes in the GnomAD database, including 127,914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10734 hom., cov: 32)
  • Exomes 𝑓: 0.40 (117180 hom.)
• Consequence: GRM7 NM_000844.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.466

Genes affected

GRM7 (HGNC:4599): (glutamate metabotropic receptor 7) L-glutamate is the major excitatory neurotransmitter in the central nervous system, and it 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 three 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. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 3-6861610-C-T is Benign according to our data. Variant chr3-6861610-C-T is described in ClinVar as [Benign]. Clinvar id is 1164859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.466 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.54 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM7	NM_000844.4	c.222C>T	p.Asn74=	synonymous_variant	1/10	ENST00000357716.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM7	ENST00000357716.9	c.222C>T	p.Asn74=	synonymous_variant	1/10	1	NM_000844.4	P1

Frequencies

GnomAD3 genomes AF: 0.373 AC: 56621 AN: 151846 Hom.: 10726 Cov.: 32

Gnomad AFR AF: 0.329

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.398

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.361

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.388

Gnomad OTH AF: 0.391

GnomAD3 exomes AF: 0.400 AC: 98027 AN: 244934 Hom.: 20105 AF XY: 0.409 AC XY: 54348 AN XY: 132730

Gnomad AFR exome AF: 0.331

Gnomad AMR exome AF: 0.405

Gnomad ASJ exome AF: 0.405

Gnomad EAS exome AF: 0.287

Gnomad SAS exome AF: 0.563

Gnomad FIN exome AF: 0.366

Gnomad NFE exome AF: 0.388

Gnomad OTH exome AF: 0.402

GnomAD4 exome AF: 0.398 AC: 580961 AN: 1458514 Hom.: 117180 Cov.: 44 AF XY: 0.404 AC XY: 292649 AN XY: 725220

Gnomad4 AFR exome AF: 0.333

Gnomad4 AMR exome AF: 0.405

Gnomad4 ASJ exome AF: 0.406

Gnomad4 EAS exome AF: 0.317

Gnomad4 SAS exome AF: 0.559

Gnomad4 FIN exome AF: 0.369

Gnomad4 NFE exome AF: 0.391

Gnomad4 OTH exome AF: 0.399

GnomAD4 genome AF: 0.373 AC: 56650 AN: 151964 Hom.: 10734 Cov.: 32 AF XY: 0.376 AC XY: 27943 AN XY: 74284

Gnomad4 AFR AF: 0.329

Gnomad4 AMR AF: 0.397

Gnomad4 ASJ AF: 0.396

Gnomad4 EAS AF: 0.304

Gnomad4 SAS AF: 0.557

Gnomad4 FIN AF: 0.361

Gnomad4 NFE AF: 0.388

Gnomad4 OTH AF: 0.393

Alfa AF: 0.387 Hom.: 16013

Bravo AF: 0.368

Asia WGS AF: 0.425 AC: 1476 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GRM7-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	9.5
Dann	Benign	0.94

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: rs3749380; hg19: chr3-6903297; COSMIC: COSV63177511; COSMIC: COSV63177511;