rs2875257

Variant names:

• chr3-7179403-G-A
• rs2875257
• NM_000844.4:c.736+32735G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000844.4(GRM7):​c.736+32735G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 152,062 control chromosomes in the GnomAD database, including 9,452 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.34 (9452 hom., cov: 33)
• Consequence: GRM7 NM_000844.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0990
• Publications: 3 publications found

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]

GRM7 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM7	NM_000844.4	c.736+32735G>A		intron_variant	Intron 2 of 9	ENST00000357716.9	NP_000835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM7	ENST00000357716.9	c.736+32735G>A		intron_variant	Intron 2 of 9	1	NM_000844.4	ENSP00000350348.4
GRM7	ENST00000440923.7	n.736+32735G>A		intron_variant	Intron 2 of 11	2		ENSP00000412329.3

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51304 AN: 151944 Hom.: 9421 Cov.: 33

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.284

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.338 AC: 51377 AN: 152062 Hom.: 9452 Cov.: 33 AF XY: 0.331 AC XY: 24634 AN XY: 74336

African (AFR) AF: 0.489 AC: 20283 AN: 41486

American (AMR) AF: 0.200 AC: 3049 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 595 AN: 3470

East Asian (EAS) AF: 0.211 AC: 1090 AN: 5166

South Asian (SAS) AF: 0.263 AC: 1267 AN: 4820

European-Finnish (FIN) AF: 0.327 AC: 3456 AN: 10564

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.305 AC: 20748 AN: 67958

Other (OTH) AF: 0.286 AC: 604 AN: 2112

Alfa AF: 0.319 Hom.: 1421

Bravo AF: 0.331

Asia WGS AF: 0.311 AC: 1083 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.7
DANN	Benign	0.61
PhyloP100		-0.099
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2875257; hg19: chr3-7221090;