rs2229901

Positions:

• chr6-34022670-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000841.4(GRM4):​c.*151A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 674,752 control chromosomes in the GnomAD database, including 24,904 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 0.32 (10903 hom., cov: 32)
  • Exomes 𝑓: 0.21 (14001 hom.)
• Consequence: GRM4 NM_000841.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.250

Genes affected

GRM4 (HGNC:4596): (glutamate metabotropic receptor 4) L-glutamate is the major excitatory neurotransmitter in the central nervous system and 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 3 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. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

GRM4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM4	NM_000841.4	c.*151A>G		3_prime_UTR_variant	11/11	ENST00000538487.7	NP_000832.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRM4	ENST00000538487.7	c.*151A>G		3_prime_UTR_variant	11/11	2	NM_000841.4	ENSP00000440556.1

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48247 AN: 152040 Hom.: 10856 Cov.: 32

Gnomad AFR AF: 0.638

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.311

GnomAD4 exome AF: 0.210 AC: 109656 AN: 522594 Hom.: 14001 Cov.: 6 AF XY: 0.211 AC XY: 58182 AN XY: 276146

Gnomad4 AFR exome AF: 0.645

Gnomad4 AMR exome AF: 0.251

Gnomad4 ASJ exome AF: 0.163

Gnomad4 EAS exome AF: 0.332

Gnomad4 SAS exome AF: 0.281

Gnomad4 FIN exome AF: 0.173

Gnomad4 NFE exome AF: 0.166

Gnomad4 OTH exome AF: 0.232

GnomAD4 genome AF: 0.318 AC: 48344 AN: 152158 Hom.: 10903 Cov.: 32 AF XY: 0.315 AC XY: 23464 AN XY: 74408

Gnomad4 AFR AF: 0.638

Gnomad4 AMR AF: 0.254

Gnomad4 ASJ AF: 0.163

Gnomad4 EAS AF: 0.378

Gnomad4 SAS AF: 0.294

Gnomad4 FIN AF: 0.183

Gnomad4 NFE AF: 0.165

Gnomad4 OTH AF: 0.312

Alfa AF: 0.194 Hom.: 5228

Bravo AF: 0.338

Asia WGS AF: 0.381 AC: 1323 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.3
DANN	Benign	0.75

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: rs2229901; hg19: chr6-33990447; COSMIC: COSV65218912; COSMIC: COSV65218912;