chr7-127224625-T-G

Variant names:

• chr7-127224625-T-G
• rs4532535
• NM_000845.3:c.510+18070A>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.510+18070A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 152,036 control chromosomes in the GnomAD database, including 29,378 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 0.59 (29378 hom., cov: 32)
• Consequence: GRM8 NM_000845.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.407
• 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]

GRM8-AS1 (HGNC:40268): (GRM8 antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.881 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM8	NM_000845.3	c.510+18070A>C		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.510+18070A>C		intron_variant	Intron 2 of 10	5	NM_000845.3	ENSP00000344173.2

Frequencies

GnomAD3 genomes AF: 0.591 AC: 89759 AN: 151918 Hom.: 29324 Cov.: 32

Gnomad AFR AF: 0.889

Gnomad AMI AF: 0.655

Gnomad AMR AF: 0.464

Gnomad ASJ AF: 0.531

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.465

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.495

Gnomad OTH AF: 0.582

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

GnomAD4 genome AF: 0.591 AC: 89864 AN: 152036 Hom.: 29378 Cov.: 32 AF XY: 0.582 AC XY: 43250 AN XY: 74334

African (AFR) AF: 0.889 AC: 36892 AN: 41496

American (AMR) AF: 0.463 AC: 7071 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.531 AC: 1842 AN: 3466

East Asian (EAS) AF: 0.255 AC: 1319 AN: 5166

South Asian (SAS) AF: 0.460 AC: 2215 AN: 4820

European-Finnish (FIN) AF: 0.465 AC: 4908 AN: 10548

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.495 AC: 33618 AN: 67958

Other (OTH) AF: 0.577 AC: 1218 AN: 2110

Alfa AF: 0.554 Hom.: 3093

Bravo AF: 0.604

Asia WGS AF: 0.400 AC: 1395 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.28
DANN	Benign	0.36
PhyloP100		-0.41
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: rs4532535; hg19: chr7-126864679; COSMIC: COSV58844849;