NM_000844.4:c.519+3599A>G

Variant names:

• chr3-6865506-A-G
• rs6443074
• NM_000844.4:c.519+3599A>G

Variant summary

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

The NM_000844.4(GRM7):​c.519+3599A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0566 in 151,816 control chromosomes in the GnomAD database, including 305 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 0.057 (305 hom., cov: 32)
• Consequence: GRM7 NM_000844.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0850
• Publications: 2 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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0792 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM7	NM_000844.4	c.519+3599A>G		intron_variant	Intron 1 of 9	ENST00000357716.9	NP_000835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM7	ENST00000357716.9	c.519+3599A>G		intron_variant	Intron 1 of 9	1	NM_000844.4	ENSP00000350348.4
GRM7	ENST00000440923.7	n.519+3599A>G		intron_variant	Intron 1 of 11	2		ENSP00000412329.3

Frequencies

GnomAD3 genomes AF: 0.0567 AC: 8603 AN: 151726 Hom.: 307 Cov.: 32

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.0518

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.0330

Gnomad FIN AF: 0.0649

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.0810

Gnomad OTH AF: 0.0605

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

GnomAD4 genome AF: 0.0566 AC: 8593 AN: 151816 Hom.: 305 Cov.: 32 AF XY: 0.0552 AC XY: 4092 AN XY: 74142

African (AFR) AF: 0.0200 AC: 827 AN: 41416

American (AMR) AF: 0.0517 AC: 789 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 399 AN: 3466

East Asian (EAS) AF: 0.000584 AC: 3 AN: 5138

South Asian (SAS) AF: 0.0323 AC: 155 AN: 4796

European-Finnish (FIN) AF: 0.0649 AC: 679 AN: 10466

Middle Eastern (MID) AF: 0.0719 AC: 21 AN: 292

European-Non Finnish (NFE) AF: 0.0810 AC: 5505 AN: 67964

Other (OTH) AF: 0.0589 AC: 124 AN: 2104

Alfa AF: 0.0765 Hom.: 278

Bravo AF: 0.0549

Asia WGS AF: 0.0200 AC: 70 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.5
DANN	Benign	0.70
PhyloP100		-0.085
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: rs6443074; hg19: chr3-6907193;