6-34047988-C-T

Position:

• chr6-34047988-C-T

Variant summary

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

The NM_000841.4(GRM4):​c.1169-7240G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 152,116 control chromosomes in the GnomAD database, including 5,565 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 0.25 (5565 hom., cov: 32)
• Consequence: GRM4 NM_000841.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.88

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]

ACMG classification

Verdict is Benign. Variant got -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 = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM4	NM_000841.4	c.1169-7240G>A		intron_variant		ENST00000538487.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM4	ENST00000538487.7	c.1169-7240G>A		intron_variant		2	NM_000841.4	P1

Frequencies

GnomAD3 genomes AF: 0.250 AC: 38020 AN: 151998 Hom.: 5571 Cov.: 32

Gnomad AFR AF: 0.401

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.258

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

GnomAD4 genome AF: 0.250 AC: 38015 AN: 152116 Hom.: 5565 Cov.: 32 AF XY: 0.247 AC XY: 18379 AN XY: 74362

Gnomad4 AFR AF: 0.401

Gnomad4 AMR AF: 0.224

Gnomad4 ASJ AF: 0.161

Gnomad4 EAS AF: 0.316

Gnomad4 SAS AF: 0.245

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.180

Gnomad4 OTH AF: 0.259

Alfa AF: 0.195 Hom.: 5814

Bravo AF: 0.264

Asia WGS AF: 0.306 AC: 1064 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	8.6
DANN	Benign	0.43

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: rs4711374; hg19: chr6-34015765;