7-127058297-A-C

Variant names:

• chr7-127058297-A-C
• rs11563750
• NM_000845.3:c.727+48199T>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.727+48199T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0745 in 359,654 control chromosomes in the GnomAD database, including 1,247 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 0.080 (526 hom., cov: 33)
  • Exomes 𝑓: 0.071 (721 hom.)
• Consequence: GRM8 NM_000845.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.199
• 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]

MIR592 (HGNC:32848): (microRNA 592) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000845.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM8	NM_000845.3	MANE Select	c.727+48199T>G		intron	N/A	NP_000836.2
	GRM8	NM_001371086.1		c.727+48199T>G		intron	N/A	NP_001358015.1
	GRM8	NM_001127323.1		c.727+48199T>G		intron	N/A	NP_001120795.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM8	ENST00000339582.7	TSL:5 MANE Select	c.727+48199T>G		intron	N/A	ENSP00000344173.2
	GRM8	ENST00000358373.8	TSL:1	c.727+48199T>G		intron	N/A	ENSP00000351142.3
	GRM8	ENST00000341617.7	TSL:1	n.727+48199T>G		intron	N/A	ENSP00000345747.3

Frequencies

GnomAD3 genomes AF: 0.0797 AC: 12130 AN: 152210 Hom.: 522 Cov.: 33

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0841

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.0552

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0574

Gnomad OTH AF: 0.0837

GnomAD4 exome AF: 0.0706 AC: 14645 AN: 207326 Hom.: 721 AF XY: 0.0758 AC XY: 9180 AN XY: 121062

African (AFR) AF: 0.102 AC: 240 AN: 2360

American (AMR) AF: 0.0664 AC: 380 AN: 5726

Ashkenazi Jewish (ASJ) AF: 0.0993 AC: 781 AN: 7864

East Asian (EAS) AF: 0.0949 AC: 234 AN: 2466

South Asian (SAS) AF: 0.117 AC: 4865 AN: 41602

European-Finnish (FIN) AF: 0.0547 AC: 785 AN: 14346

Middle Eastern (MID) AF: 0.0542 AC: 135 AN: 2490

European-Non Finnish (NFE) AF: 0.0539 AC: 6492 AN: 120360

Other (OTH) AF: 0.0725 AC: 733 AN: 10112

GnomAD4 genome AF: 0.0798 AC: 12159 AN: 152328 Hom.: 526 Cov.: 33 AF XY: 0.0813 AC XY: 6058 AN XY: 74494

African (AFR) AF: 0.111 AC: 4614 AN: 41564

American (AMR) AF: 0.0846 AC: 1295 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 366 AN: 3472

East Asian (EAS) AF: 0.110 AC: 569 AN: 5190

South Asian (SAS) AF: 0.126 AC: 609 AN: 4828

European-Finnish (FIN) AF: 0.0552 AC: 586 AN: 10622

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0574 AC: 3903 AN: 68026

Other (OTH) AF: 0.0837 AC: 177 AN: 2114

Alfa AF: 0.0738 Hom.: 76

Bravo AF: 0.0839

Asia WGS AF: 0.111 AC: 386 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.3
DANN	Benign	0.72
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: rs11563750; hg19: chr7-126698351;