3-7146493-T-C

Position:

• chr3-7146493-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000844.4(GRM7):​c.561T>C​(p.Ser187=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00961 in 1,613,844 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0097 (111 hom.)
• Consequence: GRM7 NM_000844.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.803

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 3-7146493-T-C is Benign according to our data. Variant chr3-7146493-T-C is described in ClinVar as [Benign]. Clinvar id is 709766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.803 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0084 (1279/152230) while in subpopulation NFE AF= 0.0127 (863/68016). AF 95% confidence interval is 0.012. There are 14 homozygotes in gnomad4. There are 647 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM7	NM_000844.4	c.561T>C	p.Ser187=	synonymous_variant	2/10	ENST00000357716.9	NP_000835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRM7	ENST00000357716.9	c.561T>C	p.Ser187=	synonymous_variant	2/10	1	NM_000844.4	ENSP00000350348	P1

Frequencies

GnomAD3 genomes AF: 0.00841 AC: 1280 AN: 152112 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00793

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00873 AC: 2194 AN: 251262 Hom.: 13 AF XY: 0.00858 AC XY: 1165 AN XY: 135798

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00538

Gnomad ASJ exome AF: 0.0165

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.0136

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.00974 AC: 14234 AN: 1461614 Hom.: 111 Cov.: 32 AF XY: 0.00945 AC XY: 6868 AN XY: 727112

Gnomad4 AFR exome AF: 0.00129

Gnomad4 AMR exome AF: 0.00557

Gnomad4 ASJ exome AF: 0.0166

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00139

Gnomad4 FIN exome AF: 0.0136

Gnomad4 NFE exome AF: 0.0108

Gnomad4 OTH exome AF: 0.0101

GnomAD4 genome AF: 0.00840 AC: 1279 AN: 152230 Hom.: 14 Cov.: 32 AF XY: 0.00869 AC XY: 647 AN XY: 74426

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00792

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0127

Gnomad4 NFE AF: 0.0127

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.0115 Hom.: 6

Bravo AF: 0.00784

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.0133

EpiControl AF: 0.0107

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	GRM7: BP4, BP7, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.2
DANN	Benign	0.39

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: rs35106713; hg19: chr3-7188180; COSMIC: COSV63143571;