rs6951643

Positions:

• chr7-126789463-A-G
• chr7-126789463-A-T

Variant summary

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

The NM_000845.3(GRM8):​c.1157-19398T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.474 in 151,990 control chromosomes in the GnomAD database, including 17,687 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 0.47 (17687 hom., cov: 32)
• Consequence: GRM8 NM_000845.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.883

Genes affected

GRM8 (HGNC:4600): (glutamate metabotropic receptor 8) 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. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

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 = 0.552 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM8	NM_000845.3	c.1157-19398T>C		intron_variant		ENST00000339582.7	NP_000836.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRM8	ENST00000339582.7	c.1157-19398T>C		intron_variant		5	NM_000845.3	ENSP00000344173	P1

Frequencies

GnomAD3 genomes AF: 0.474 AC: 71944 AN: 151872 Hom.: 17653 Cov.: 32

Gnomad AFR AF: 0.558

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.422

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.0783

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.530

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.457

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

GnomAD4 genome AF: 0.474 AC: 72030 AN: 151990 Hom.: 17687 Cov.: 32 AF XY: 0.473 AC XY: 35140 AN XY: 74278

Gnomad4 AFR AF: 0.558

Gnomad4 AMR AF: 0.423

Gnomad4 ASJ AF: 0.393

Gnomad4 EAS AF: 0.0781

Gnomad4 SAS AF: 0.378

Gnomad4 FIN AF: 0.530

Gnomad4 NFE AF: 0.469

Gnomad4 OTH AF: 0.455

Alfa AF: 0.452 Hom.: 32665

Bravo AF: 0.467

Asia WGS AF: 0.266 AC: 929 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	0.028
DANN	Benign	0.29

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: rs6951643; hg19: chr7-126429517;