NM_000845.3:c.1358-74478T>C

Variant names:

• chr7-126683976-A-G
• rs4731323
• NM_000845.3:c.1358-74478T>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.1358-74478T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 152,212 control chromosomes in the GnomAD database, including 3,419 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 0.21 (3419 hom., cov: 32)
• Consequence: GRM8 NM_000845.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.205
• 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM8	NM_000845.3	c.1358-74478T>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.1358-74478T>C		intron_variant	Intron 7 of 10	5	NM_000845.3	ENSP00000344173.2

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31252 AN: 152094 Hom.: 3414 Cov.: 32

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.0460

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.220

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.202

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

GnomAD4 genome AF: 0.206 AC: 31298 AN: 152212 Hom.: 3419 Cov.: 32 AF XY: 0.203 AC XY: 15144 AN XY: 74426

African (AFR) AF: 0.192 AC: 7991 AN: 41536

American (AMR) AF: 0.216 AC: 3303 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 762 AN: 3472

East Asian (EAS) AF: 0.0459 AC: 238 AN: 5180

South Asian (SAS) AF: 0.224 AC: 1080 AN: 4820

European-Finnish (FIN) AF: 0.171 AC: 1814 AN: 10598

Middle Eastern (MID) AF: 0.233 AC: 68 AN: 292

European-Non Finnish (NFE) AF: 0.227 AC: 15446 AN: 68000

Other (OTH) AF: 0.201 AC: 424 AN: 2114

Alfa AF: 0.221 Hom.: 11631

Bravo AF: 0.209

Asia WGS AF: 0.142 AC: 494 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.71
DANN	Benign	0.68
PhyloP100		-0.20
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: rs4731323; hg19: chr7-126324030;