rs1419437

Variant names:

• chr7-127020051-A-G
• rs1419437
• NM_000845.3:c.727+86445T>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.727+86445T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 152,008 control chromosomes in the GnomAD database, including 10,260 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 0.36 (10260 hom., cov: 33)
• Consequence: GRM8 NM_000845.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.443
• Publications: 3 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM8	NM_000845.3	c.727+86445T>C		intron_variant	Intron 3 of 10	ENST00000339582.7	NP_000836.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM8	ENST00000339582.7	c.727+86445T>C		intron_variant	Intron 3 of 10	5	NM_000845.3	ENSP00000344173.2

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54333 AN: 151890 Hom.: 10244 Cov.: 33

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.416

Gnomad OTH AF: 0.396

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

GnomAD4 genome AF: 0.358 AC: 54377 AN: 152008 Hom.: 10260 Cov.: 33 AF XY: 0.354 AC XY: 26321 AN XY: 74296

African (AFR) AF: 0.248 AC: 10283 AN: 41486

American (AMR) AF: 0.371 AC: 5664 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 1758 AN: 3466

East Asian (EAS) AF: 0.340 AC: 1758 AN: 5164

South Asian (SAS) AF: 0.371 AC: 1787 AN: 4820

European-Finnish (FIN) AF: 0.338 AC: 3578 AN: 10578

Middle Eastern (MID) AF: 0.387 AC: 113 AN: 292

European-Non Finnish (NFE) AF: 0.416 AC: 28241 AN: 67910

Other (OTH) AF: 0.400 AC: 842 AN: 2106

Alfa AF: 0.385 Hom.: 1879

Bravo AF: 0.359

Asia WGS AF: 0.361 AC: 1255 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.80
DANN	Benign	0.40
PhyloP100		-0.44
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: rs1419437; hg19: chr7-126660105;