rs17691394

Variant names:

• chr7-126684537-A-G
• rs17691394
• NM_000845.3:c.1358-75039T>C

Variant summary

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

The NM_000845.3(GRM8):​c.1358-75039T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 152,192 control chromosomes in the GnomAD database, including 1,753 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 0.13 (1753 hom., cov: 32)
• Consequence: GRM8 NM_000845.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.652
• Publications: 15 publications found

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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM8	NM_000845.3	c.1358-75039T>C		intron_variant	Intron 7 of 10	ENST00000339582.7	NP_000836.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM8	ENST00000339582.7	c.1358-75039T>C		intron_variant	Intron 7 of 10	5	NM_000845.3	ENSP00000344173.2

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20065 AN: 152074 Hom.: 1753 Cov.: 32

Gnomad AFR AF: 0.0545

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0735

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.127

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

GnomAD4 genome AF: 0.132 AC: 20057 AN: 152192 Hom.: 1753 Cov.: 32 AF XY: 0.135 AC XY: 10049 AN XY: 74390

African (AFR) AF: 0.0543 AC: 2256 AN: 41542

American (AMR) AF: 0.111 AC: 1702 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 574 AN: 3464

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5174

South Asian (SAS) AF: 0.0729 AC: 352 AN: 4828

European-Finnish (FIN) AF: 0.297 AC: 3147 AN: 10580

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.172 AC: 11686 AN: 67984

Other (OTH) AF: 0.125 AC: 265 AN: 2116

Alfa AF: 0.147 Hom.: 4385

Bravo AF: 0.115

Asia WGS AF: 0.0330 AC: 113 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.8
DANN	Benign	0.76
PhyloP100		0.65
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: rs17691394; hg19: chr7-126324591;