rs10954143

Variant names:

• chr7-127088358-T-C
• rs10954143
• NM_000845.3:c.727+18138A>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+18138A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 152,138 control chromosomes in the GnomAD database, including 38,611 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 0.70 (38611 hom., cov: 33)
• Consequence: GRM8 NM_000845.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.196
• Publications: 0 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 (AFR) allele frequency at 95% confidence interval = 0.822 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM8	NM_000845.3	MANE Select	c.727+18138A>G		intron	N/A	NP_000836.2	O00222-1
	GRM8	NM_001371086.1		c.727+18138A>G		intron	N/A	NP_001358015.1	A0A9L9PYG5
	GRM8	NM_001127323.1		c.727+18138A>G		intron	N/A	NP_001120795.1	O00222-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM8	ENST00000339582.7	TSL:5 MANE Select	c.727+18138A>G		intron	N/A	ENSP00000344173.2	O00222-1
	GRM8	ENST00000358373.8	TSL:1	c.727+18138A>G		intron	N/A	ENSP00000351142.3	O00222-2
	GRM8	ENST00000341617.7	TSL:1	n.727+18138A>G		intron	N/A	ENSP00000345747.3	O00222-3

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106632 AN: 152020 Hom.: 38569 Cov.: 33

Gnomad AFR AF: 0.829

Gnomad AMI AF: 0.784

Gnomad AMR AF: 0.547

Gnomad ASJ AF: 0.732

Gnomad EAS AF: 0.342

Gnomad SAS AF: 0.655

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.712

Gnomad OTH AF: 0.707

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

GnomAD4 genome AF: 0.702 AC: 106727 AN: 152138 Hom.: 38611 Cov.: 33 AF XY: 0.688 AC XY: 51151 AN XY: 74346

African (AFR) AF: 0.829 AC: 34418 AN: 41522

American (AMR) AF: 0.547 AC: 8356 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.732 AC: 2540 AN: 3472

East Asian (EAS) AF: 0.342 AC: 1770 AN: 5174

South Asian (SAS) AF: 0.655 AC: 3153 AN: 4816

European-Finnish (FIN) AF: 0.534 AC: 5628 AN: 10546

Middle Eastern (MID) AF: 0.752 AC: 221 AN: 294

European-Non Finnish (NFE) AF: 0.712 AC: 48428 AN: 68000

Other (OTH) AF: 0.709 AC: 1498 AN: 2112

Alfa AF: 0.715 Hom.: 5083

Bravo AF: 0.703

Asia WGS AF: 0.538 AC: 1871 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.4
DANN	Benign	0.52
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: rs10954143; hg19: chr7-126728412;