chr3-6861471-TGGC-T

Position:

• chr3-6861471-TGGC-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PM4_Supporting BS1_Supporting

The NM_000844.4(GRM7):​c.94_96del​(p.Ala32del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000514 in 1,284,560 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000063 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (1 hom.)
• Consequence: GRM7 NM_000844.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.74

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000844.4. Strenght limited to Supporting due to length of the change: 1aa.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000632 (9/142492) while in subpopulation EAS AF= 0.000768 (3/3904). AF 95% confidence interval is 0.000209. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM7	NM_000844.4	c.94_96del	p.Ala32del	inframe_deletion	1/10	ENST00000357716.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM7	ENST00000357716.9	c.94_96del	p.Ala32del	inframe_deletion	1/10	1	NM_000844.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000632 AC: 9 AN: 142344 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000768

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000110

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000464

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000966 AC: 20 AN: 206984 Hom.: 1 AF XY: 0.0000701 AC XY: 8 AN XY: 114140

Gnomad AFR exome AF: 0.0000787

Gnomad AMR exome AF: 0.0000355

Gnomad ASJ exome AF: 0.000126

Gnomad EAS exome AF: 0.0000647

Gnomad SAS exome AF: 0.000192

Gnomad FIN exome AF: 0.000108

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000499 AC: 57 AN: 1142068 Hom.: 1 AF XY: 0.0000405 AC XY: 23 AN XY: 568466

Gnomad4 AFR exome AF: 0.0000403

Gnomad4 AMR exome AF: 0.0000307

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000321

Gnomad4 SAS exome AF: 0.000125

Gnomad4 FIN exome AF: 0.000288

Gnomad4 NFE exome AF: 0.0000302

Gnomad4 OTH exome AF: 0.0000720

GnomAD4 genome AF: 0.0000632 AC: 9 AN: 142492 Hom.: 0 Cov.: 32 AF XY: 0.0000722 AC XY: 5 AN XY: 69292

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000138

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000768

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000110

Gnomad4 NFE AF: 0.0000464

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000182 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 04, 2022

This variant, c.94_96del, results in the deletion of 1 amino acid(s) of the GRM7 protein (p.Ala32del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with GRM7-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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: rs752881858; hg19: chr3-6903158;