3-6861469-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_000844.4(GRM7):c.81G>C(p.Ala27=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000512 in 1,590,576 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (4 hom.)
• Consequence: GRM7 NM_000844.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.69

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 3-6861469-G-C is Benign according to our data. Variant chr3-6861469-G-C is described in ClinVar as [Benign]. Clinvar id is 722285.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.69 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00288 (439/152186) while in subpopulation AFR AF= 0.0101 (420/41580). AF 95% confidence interval is 0.0093. There are 2 homozygotes in gnomad4. There are 213 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM7	NM_000844.4	c.81G>C	p.Ala27=	synonymous_variant	1/10	ENST00000357716.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM7	ENST00000357716.9	c.81G>C	p.Ala27=	synonymous_variant	1/10	1	NM_000844.4	P1

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 439 AN: 152068 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000727 AC: 151 AN: 207800 Hom.: 0 AF XY: 0.000549 AC XY: 63 AN XY: 114762

Gnomad AFR exome AF: 0.0108

Gnomad AMR exome AF: 0.000284

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000320

Gnomad OTH exome AF: 0.000596

GnomAD4 exome AF: 0.000261 AC: 375 AN: 1438390 Hom.: 4 Cov.: 34 AF XY: 0.000210 AC XY: 150 AN XY: 714768

Gnomad4 AFR exome AF: 0.0101

Gnomad4 AMR exome AF: 0.000430

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000241

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000544

Gnomad4 OTH exome AF: 0.000303

GnomAD4 genome AF: 0.00288 AC: 439 AN: 152186 Hom.: 2 Cov.: 32 AF XY: 0.00286 AC XY: 213 AN XY: 74392

Gnomad4 AFR AF: 0.0101

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000262 Hom.: 0

Bravo AF: 0.00307

Asia WGS AF: 0.00144 AC: 5 AN: 3478

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

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	12
Dann	Benign	0.59

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: rs138762445; hg19: chr3-6903156;