rs1557644

Variant names:

• chr7-127106997-T-C
• rs1557644
• NM_000845.3:c.511-285A>G

Variant summary

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

The NM_000845.3(GRM8):​c.511-285A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 152,064 control chromosomes in the GnomAD database, including 4,595 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 0.23 (4595 hom., cov: 32)
• Consequence: GRM8 NM_000845.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0520
• Publications: 2 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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM8	NM_000845.3	c.511-285A>G		intron_variant	Intron 2 of 10	ENST00000339582.7	NP_000836.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM8	ENST00000339582.7	c.511-285A>G		intron_variant	Intron 2 of 10	5	NM_000845.3	ENSP00000344173.2

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34599 AN: 151948 Hom.: 4594 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.0991

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.249

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

GnomAD4 genome AF: 0.228 AC: 34596 AN: 152064 Hom.: 4595 Cov.: 32 AF XY: 0.220 AC XY: 16358 AN XY: 74334

African (AFR) AF: 0.108 AC: 4496 AN: 41506

American (AMR) AF: 0.178 AC: 2726 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1141 AN: 3464

East Asian (EAS) AF: 0.0985 AC: 511 AN: 5186

South Asian (SAS) AF: 0.230 AC: 1108 AN: 4822

European-Finnish (FIN) AF: 0.201 AC: 2125 AN: 10566

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.318 AC: 21576 AN: 67920

Other (OTH) AF: 0.252 AC: 532 AN: 2114

Alfa AF: 0.285 Hom.: 6675

Bravo AF: 0.221

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.2
DANN	Benign	0.68
PhyloP100		0.052
PromoterAI		0.096	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1557644; hg19: chr7-126747051;