rs3749448

Variant names:

• chr3-7146429-G-A
• rs3749448
• NM_000844.4:c.520-23G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-7146429-G-A
• chr3-7146429-G-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.520-23G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,562,530 control chromosomes in the GnomAD database, including 35,611 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 0.26 (5766 hom., cov: 32)
  • Exomes 𝑓: 0.20 (29845 hom.)
• Consequence: GRM7 NM_000844.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.980
• Publications: 13 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000844.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM7	NM_000844.4	MANE Select	c.520-23G>A		intron	N/A	NP_000835.1	Q14831-1
	GRM7	NM_181874.3		c.520-23G>A		intron	N/A	NP_870989.1	Q14831-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM7	ENST00000357716.9	TSL:1 MANE Select	c.520-23G>A		intron	N/A	ENSP00000350348.4	Q14831-1
	GRM7	ENST00000389336.8	TSL:1	c.520-23G>A		intron	N/A	ENSP00000373987.4	Q14831-5
	GRM7	ENST00000389335.7	TSL:1	n.520-23G>A		intron	N/A	ENSP00000373986.3	Q14831-4

Frequencies

GnomAD3 genomes AF: 0.257 AC: 38981 AN: 151836 Hom.: 5760 Cov.: 32

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.251

GnomAD2 exomes AF: 0.216 AC: 54027 AN: 250512 AF XY: 0.218

Gnomad AFR exome AF: 0.419

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.227

Gnomad EAS exome AF: 0.265

Gnomad FIN exome AF: 0.186

Gnomad NFE exome AF: 0.195

Gnomad OTH exome AF: 0.215

GnomAD4 exome AF: 0.199 AC: 281016 AN: 1410576 Hom.: 29845 Cov.: 25 AF XY: 0.201 AC XY: 141662 AN XY: 705000

African (AFR) AF: 0.428 AC: 13898 AN: 32496

American (AMR) AF: 0.130 AC: 5782 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 5980 AN: 25798

East Asian (EAS) AF: 0.238 AC: 9371 AN: 39444

South Asian (SAS) AF: 0.274 AC: 23305 AN: 85208

European-Finnish (FIN) AF: 0.186 AC: 9913 AN: 53380

Middle Eastern (MID) AF: 0.308 AC: 1407 AN: 4570

European-Non Finnish (NFE) AF: 0.186 AC: 198263 AN: 1066484

Other (OTH) AF: 0.224 AC: 13097 AN: 58560

GnomAD4 genome AF: 0.257 AC: 39016 AN: 151954 Hom.: 5766 Cov.: 32 AF XY: 0.254 AC XY: 18881 AN XY: 74262

African (AFR) AF: 0.417 AC: 17269 AN: 41448

American (AMR) AF: 0.177 AC: 2693 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 780 AN: 3468

East Asian (EAS) AF: 0.255 AC: 1314 AN: 5154

South Asian (SAS) AF: 0.262 AC: 1258 AN: 4796

European-Finnish (FIN) AF: 0.175 AC: 1847 AN: 10560

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.192 AC: 13066 AN: 67962

Other (OTH) AF: 0.253 AC: 533 AN: 2110

Alfa AF: 0.212 Hom.: 14882

Bravo AF: 0.265

Asia WGS AF: 0.250 AC: 869 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.55
DANN	Benign	0.85
PhyloP100		-0.98
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3749448;

hg19: chr3-7188116;

COSMIC: COSV107435994;