3-7414988-C-T

Variant names:

• chr3-7414988-C-T
• rs712774
• NM_000844.4:c.1034-35C>T

Variant summary

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

The NM_000844.4(GRM7):​c.1034-35C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.723 in 1,558,222 control chromosomes in the GnomAD database, including 410,241 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 0.74 (41504 hom., cov: 30)
  • Exomes 𝑓: 0.72 (368737 hom.)
• Consequence: GRM7 NM_000844.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.97
• Publications: 10 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM7	NM_000844.4	c.1034-35C>T		intron_variant	Intron 4 of 9	ENST00000357716.9	NP_000835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM7	ENST00000357716.9	c.1034-35C>T		intron_variant	Intron 4 of 9	1	NM_000844.4	ENSP00000350348.4
GRM7	ENST00000440923.7	n.1034-35C>T		intron_variant	Intron 4 of 11	2		ENSP00000412329.3

Frequencies

GnomAD3 genomes AF: 0.735 AC: 111502 AN: 151730 Hom.: 41449 Cov.: 30

Gnomad AFR AF: 0.829

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.625

Gnomad ASJ AF: 0.711

Gnomad EAS AF: 0.537

Gnomad SAS AF: 0.694

Gnomad FIN AF: 0.691

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.728

Gnomad OTH AF: 0.721

GnomAD2 exomes AF: 0.689 AC: 155322 AN: 225290 AF XY: 0.694

Gnomad AFR exome AF: 0.836

Gnomad AMR exome AF: 0.521

Gnomad ASJ exome AF: 0.713

Gnomad EAS exome AF: 0.548

Gnomad FIN exome AF: 0.679

Gnomad NFE exome AF: 0.731

Gnomad OTH exome AF: 0.703

GnomAD4 exome AF: 0.722 AC: 1014867 AN: 1406374 Hom.: 368737 Cov.: 23 AF XY: 0.721 AC XY: 503358 AN XY: 697958

African (AFR) AF: 0.837 AC: 26141 AN: 31216

American (AMR) AF: 0.534 AC: 20570 AN: 38512

Ashkenazi Jewish (ASJ) AF: 0.713 AC: 17579 AN: 24654

East Asian (EAS) AF: 0.559 AC: 21258 AN: 38058

South Asian (SAS) AF: 0.699 AC: 56074 AN: 80212

European-Finnish (FIN) AF: 0.677 AC: 35648 AN: 52658

Middle Eastern (MID) AF: 0.743 AC: 4032 AN: 5428

European-Non Finnish (NFE) AF: 0.735 AC: 791732 AN: 1077610

Other (OTH) AF: 0.721 AC: 41833 AN: 58026

GnomAD4 genome AF: 0.735 AC: 111615 AN: 151848 Hom.: 41504 Cov.: 30 AF XY: 0.731 AC XY: 54221 AN XY: 74202

African (AFR) AF: 0.829 AC: 34353 AN: 41458

American (AMR) AF: 0.625 AC: 9506 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.711 AC: 2467 AN: 3470

East Asian (EAS) AF: 0.537 AC: 2757 AN: 5136

South Asian (SAS) AF: 0.695 AC: 3337 AN: 4802

European-Finnish (FIN) AF: 0.691 AC: 7281 AN: 10538

Middle Eastern (MID) AF: 0.741 AC: 218 AN: 294

European-Non Finnish (NFE) AF: 0.728 AC: 49464 AN: 67916

Other (OTH) AF: 0.724 AC: 1525 AN: 2106

Alfa AF: 0.723 Hom.: 7994

Bravo AF: 0.735

Asia WGS AF: 0.676 AC: 2350 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.0030
DANN	Benign	0.79
PhyloP100		-4.0
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: rs712774; hg19: chr3-7456675; COSMIC: COSV63178920;